Benzoxazepin PI3K inhibitor compounds and methods of use

ABSTRACT

Benzoxazepin compounds of Formula I, including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, wherein: Z 1  is CR 1  or N; Z 2  is CR 2  or N; Z 3  is CR 3  or N; Z 4  is CR 4  or N; and B is a pyrazolyl, imidazolyl, or triazolyl ring fused to the benzoxepin ring, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 13/681,763, filed 20Nov. 2012, now U.S. Pat. No. 8,586,574, which is a continuation of U.S.Ser. No. 13/477,587, filed 22 May 2012, now U.S. Pat. No. 8,343,955,issued 1 Jan. 2013, which is a divisional of U.S. Ser. No. 12/890,812,filed 27 Sep. 2010, now U.S. Pat. No. 8,242,104, issued 14 Aug. 2012,and claims the benefit under 35 USC §119(e) of U.S. ProvisionalApplication Ser. No. 61/246,381 filed on 28 Sep. 2009 and U.S.Provisional Application Ser. No. 61/330,685 filed on 3 May 2010, all ofwhich are incorporated by reference in entireties.

FIELD OF THE INVENTION

The invention relates generally to compounds with anti-cancer activityand more specifically to compounds which inhibit PI3 kinase activity.The invention also relates to methods of using the compounds for invitro, in situ, and in vivo diagnosis or treatment of mammalian cells,or associated pathological conditions.

BACKGROUND OF THE INVENTION

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of anumber of phospholipids found in cell membranes. In recent years it hasbecome clear that PI plays an important role in intracellular signaltransduction. Cell signaling via 3′-phosphorylated phosphoinositides hasbeen implicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity(Rameh et al (1999) J. Biol Chem, 274:8347-8350). The enzyme responsiblefor generating these phosphorylated signaling products,phosphatidylinositol 3-kinase (also referred to as PI 3-kinase or PI3K),was originally identified as an activity associated with viraloncoproteins and growth factor receptor tyrosine kinases thatphosphorylate phosphatidylinositol (PI) and its phosphorylatedderivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al(1992) Trends Cell Biol 2:358-60).

Phosphoinositide 3-kinases (PI3K) are lipid kinases that phosphorylatelipids at the 3-hydroxyl residue of an inositol ring (Whitman et al(1988) Nature, 332:664). The 3-phosphorylated phospholipids (PIP3s)generated by PI3-kinases act as second messengers recruiting kinaseswith lipid binding domains (including plekstrin homology (PH) regions),such as Akt and phosphoinositide-dependent kinase-1 (PDK1). Binding ofAkt to membrane PIP3s causes the translocation of Akt to the plasmamembrane, bringing Akt into contact with PDK1, which is responsible foractivating Akt. The tumor-suppressor phosphatase, PTEN, dephosphorylatesPIP3 and therefore acts as a negative regulator of Akt activation. ThePI3-kinases Akt and PDK1 are important in the regulation of manycellular processes including cell cycle regulation, proliferation,survival, apoptosis and motility and are significant components of themolecular mechanisms of diseases such as cancer, diabetes and immuneinflammation (Vivanco et al (2002) Nature Rev. Cancer 2:489; Phillips etal (1998) Cancer 83:41).

The main PI3-kinase isoform in cancer is the Class I PI3-kinase, p110 α(alpha) (U.S. Pat. Nos. 5,824,492; 5,846,824; 6,274,327). Other isoformsare implicated in cardiovascular and immune-inflammatory disease(Workman P (2004) Biochem Soc Trans 32:393-396; Patel et al (2004)Proceedings of the American Association of Cancer Research (AbstractLB-247) 95th Annual Meeting, March 27-31, Orlando, Fla., USA; Ahmadi Kand Waterfield Md. (2004) Encyclopedia of Biological Chemistry (LennarzW J, Lane M D eds) Elsevier/Academic Press).

The PI3 kinase/Akt/PTEN pathway is an attractive target for cancer drugdevelopment since such agents would be expected to inhibitproliferation, reverse the repression of apoptosis and surmountresistance to cytotoxic agents in cancer cells. PI3 kinase inhibitorshave been reported (Folkes et al (2008) J. Med. Chem. 51:5522-5532;Yaguchi et al (2006) Jour. of the Nat. Cancer Inst. 98(8):545-556; U.S.Pat. Nos. 7,173,029; 7,037,915; 6,608,056; 6,608,053; 6,838,457;6,770,641; 6,653,320; 6,403,588; 6,703,414; WO 97/15658; WO 2006/046031;WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO2004/017950; US 2004/092561; WO 2004/007491; WO 2004/006916; WO2003/037886; US 2003/149074; WO 2003/035618; WO 2003/034997; US2003/158212; EP 1417976; US 2004/053946; JP 2001247477; JP 08175990; JP08176070), including p110 alpha binding activity (US 2008/0207611; US2008/0039459; US 2008/0076768; WO 2008/073785; WO 2008/070740).

SUMMARY OF THE INVENTION

The invention relates generally to benzoxazepin compounds of Formula Iwith anti-cancer activity, and more specifically with PI3 kinaseinhibitory activity. Certain hyperproliferative disorders arecharacterized by the modulation of PI3 kinase function, e.g. bymutations or overexpression of the proteins. Accordingly, the compoundsof the invention may be useful in the treatment of hyperproliferativedisorders such as cancer. The compounds may inhibit tumor growth inmammals and may be useful for treating human cancer patients.

The invention also relates to methods of using the benzoxazepincompounds of Formula I for in vitro, in situ, and in vivo diagnosis ortreatment of mammalian cells, organisms, or associated pathologicalconditions.

Formula I compounds include:

Formula I compounds include stereoisomers, geometric isomers, tautomers,or pharmaceutically acceptable salts thereof, wherein: Z1 is CR1 or N;Z2 is CR2 or N; Z3 is CR3 or N; Z4 is CR4 or N; B is a pyrazolyl,imidazolyl, or triazolyl ring fused to the benzoxepin ring. The varioussubstituents are as defined herein.

Another aspect of the invention provides a pharmaceutical compositioncomprising a benzoxazepin compound of Formula I and a pharmaceuticallyacceptable carrier. The pharmaceutical composition may further compriseone or more additional therapeutic agent.

Another aspect of the invention provides methods of inhibiting PI3kinase activity, comprising contacting a PI3 kinase with an effectiveinhibitory amount of a compound of Formula I.

Another aspect of the invention provides methods of preventing ortreating a hyperproliferative disease or disorder modulated by PI3kinases, comprising administering to a mammal in need of such treatmentan effective amount of a compound of Formula I. Examples of suchhyperproliferative disease or disorder include, but are not limited to,cancer.

Another aspect of the invention provides methods of preventing ortreating a hyperproliferative disorder, comprising administering to amammal in need of such treatment an effective amount of a compound ofFormula I, alone or in combination with one or more additional compoundshaving anti-hyperproliferative properties.

In a further aspect the present invention provides a method of using acompound of this invention to treat a hyperproliferative disease orcondition modulated by PI3 kinase in a mammal.

An additional aspect of the invention is the use of a compound of thisinvention for treating cancer modulated by PI3 kinase in a mammal.

Another aspect of the invention includes kits comprising a compound ofFormula I, a container, and optionally a package insert or labelindicating a treatment.

Another aspect of the invention includes methods of preparing, methodsof separating, and methods of purifying compounds of Formula I.

Another aspect of the invention includes novel intermediates useful forpreparing Formula I compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a general exemplary route to benzoxepinone compounds 3

FIG. 2 shows a synthetic route to9-halo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinecompounds 12 from 4-bromo-2-hydroxybenzaldehyde 4.

FIG. 3 shows a synthetic route to7-bromo-5-chloro-2,3-dihydrobenzo[f][1,4]oxazepine 16 and7-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-imine 19

FIG. 4 shows synthetic routes to(E)-8-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine 23

FIG. 5 shows synthetic routes to10-bromo-2-phenyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 27 and10-bromo-2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine30

FIG. 6 shows a synthetic route to9-halo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinecompounds 12 from 4-bromo-2-fluorobenzonitrile 20.

FIG. 7 shows a synthetic route to9-halo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinecompounds 12 from the reaction of(E)-8-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine 23 and2-chloro-1-(1-isopropyl-1H-1,2,4-triazol-5-yl)ethanone 36.

FIG. 8 shows a synthetic route to8-chloro-3,4-dihydrooxepino[3,2-c]pyridin-5(2H)-one 42

FIG. 9 shows a synthetic route to2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol176

FIG. 10 shows conversion of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride 47 to 191, 192, 197, 198, 200.

FIG. 11 shows a synthetic route to2-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)-2-methylpropanamide205 and3-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)oxetane-3-carboxamide56 from8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride 47.

FIG. 12 shows a synthetic route to8-Azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene59.

FIG. 13 shows a synthetic route to2-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)azetidin-1-yl)ethanol169 and2-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)azetidin-1-yl)-2-methylpropan-1-ol170 from9-(azetidin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine144.

FIG. 14 shows a synthetic route to2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene68

FIG. 15 shows conversion of 68 to 175, 177, 178, 179, 189.

FIG. 16 shows a synthetic route to[4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-methanol188.

FIG. 17 shows a synthetic route to9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine239.

FIG. 18 shows a synthetic route to2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazepine88 (280).

FIG. 19 shows a synthetic route to tert-butyl5-(9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-ylcarbamatefrom 4-fluoro-2-hydroxybenzaldehyde.

FIG. 20 shows a synthetic route to10-fluoro-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine281 from 5-fluoro-2-hydroxybenzaldehyde.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.

Definitions

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms (C1-C12), wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. In anotherembodiment, an alkyl radical is one to eight carbon atoms (C1-C8), orone to six carbon atoms (C1-C6). Examples of alkyl groups include, butare not limited to, methyl (Me, —CH3), ethyl (Et, —CH2CH3), 1-propyl(n-Pr, n-propyl, —CH2CH2CH3), 2-propyl (i-Pr, i-propyl, —CH(CH3)2),1-butyl (n-Bu, n-butyl, —CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu,i-butyl, —CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, —CH(CH3)CH2CH3),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH3)3), 1-pentyl (n-pentyl,—CH2CH2CH2CH2CH3), 2-pentyl (—CH(CH3)CH2CH2CH3), 3-pentyl(—CH(CH2CH3)2), 2-methyl-2-butyl (—C(CH3)2CH2CH3), 3-methyl-2-butyl(—CH(CH3)CH(CH3)2), 3-methyl-1-butyl (—CH2CH2CH(CH3)2), 2-methyl-1-butyl(—CH2CH(CH3)CH2CH3), 1-hexyl (—CH2CH2CH2CH2CH2CH3), 2-hexyl(—CH(CH3)CH2CH2CH2CH3), 3-hexyl (—CH(CH2CH3)(CH2CH2CH3)),2-methyl-2-pentyl (—C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(—CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (—CH(CH3)CH2CH(CH3)2),3-methyl-3-pentyl (—C(CH3)(CH2CH3)2), 2-methyl-3-pentyl(—CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (—C(CH3)2CH(CH3)2),3,3-dimethyl-2-butyl (—CH(CH3)C(CH3)3, 1-heptyl, 1-octyl, and the like.

The term “alkylene” as used herein refers to a saturated linear orbranched-chain divalent hydrocarbon radical of one to twelve carbonatoms (C1-C12), wherein the alkylene radical may be optionallysubstituted independently with one or more substituents described below.In another embodiment, an alkylene radical is one to eight carbon atoms(C1-C8), or one to six carbon atoms (C1-C6). Examples of alkylene groupsinclude, but are not limited to, methylene (—CH2—), ethylene (—CH2CH2—),propylene (—CH2CH2CH2—), and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to eight carbon atoms (C2-C8) with at leastone site of unsaturation, i.e., a carbon-carbon, sp2 double bond,wherein the alkenyl radical may be optionally substituted independentlywith one or more substituents described herein, and includes radicalshaving “cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. Examples include, but are not limited to, ethylenyl orvinyl (—CH═CH2), allyl (—CH2CH═CH2), and the like.

The term “alkenylene” refers to linear or branched-chain divalenthydrocarbon radical of two to eight carbon atoms (C2-C8) with at leastone site of unsaturation, i.e., a carbon-carbon, sp2 double bond,wherein the alkenyl radical may be optionally substituted, and includesradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations. Examples include, but are not limited to,ethylenylene or vinylene (—CH═CH—), allyl (—CH2CH═CH—), and the like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to eight carbon atoms (C2-C8) with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical may be optionally substituted independently with one or moresubstituents described herein. Examples include, but are not limited to,ethynyl (—C≡CH), propynyl (propargyl, —CH2C≡CH), and the like.

The term “alkynylene” refers to a linear or branched divalenthydrocarbon radical of two to eight carbon atoms (C2-C8) with at leastone site of unsaturation, i.e., a carbon-carbon, sp triple bond, whereinthe alkynyl radical may be optionally. Examples include, but are notlimited to, ethynylene (—C≡C—), propynylene (propargylene, —CH2C≡C—),and the like.

The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and“cycloalkyl” refer to a monovalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms (C3-C12) as a monocyclicring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycleshaving 7 to 12 atoms can be arranged, e.g., as a bicyclo[4,5], [5,5],[5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ringatoms can be arranged as a bicyclo[5,6] or [6,6] system, or as bridgedsystems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms (C6-C20) derived by the removal of one hydrogen atom from a singlecarbon atom of a parent aromatic ring system. Some aryl groups arerepresented in the exemplary structures as “Ar”. Aryl includes bicyclicradicals comprising an aromatic ring fused to a saturated, partiallyunsaturated ring, or aromatic carbocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, biphenyl, indenyl,indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and thelike. Aryl groups are optionally substituted independently with one ormore substituents described herein.

“Arylene” means a divalent aromatic hydrocarbon radical of 6-20 carbonatoms (C6-C20) derived by the removal of two hydrogen atom from a twocarbon atoms of a parent aromatic ring system. Some arylene groups arerepresented in the exemplary structures as “Ar”. Arylene includesbicyclic radicals comprising an aromatic ring fused to a saturated,partially unsaturated ring, or aromatic carbocyclic ring. Typicalarylene groups include, but are not limited to, radicals derived frombenzene (phenylene), substituted benzenes, naphthalene, anthracene,biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene,1,2,3,4-tetrahydronaphthyl, and the like. Arylene groups are optionallysubstituted

The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double and/or triple bonds withinthe ring) carbocyclic radical of 3 to about 20 ring atoms in which atleast one ring atom is a heteroatom selected from nitrogen, oxygen,phosphorus and sulfur, the remaining ring atoms being C, where one ormore ring atoms is optionally substituted independently with one or moresubstituents described below. A heterocycle may be a monocycle having 3to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selectedfrom N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), e.g.:a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heterocycles aredescribed in Paquette, Leo A.; “Principles of Modern HeterocyclicChemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3,4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series ofMonographs” (John Wiley & Sons, New York, 1950 to present), inparticular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960)82:5566. “Heterocyclyl” also includes radicals where heterocycleradicals are fused with a saturated, partially unsaturated ring, oraromatic carbocyclic or heterocyclic ring. Examples of heterocyclicrings include, but are not limited to, morpholin-4-yl, piperidin-1-yl,piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl,azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl,[1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pyridyl ureas. Spiro moieties are also includedwithin the scope of this definition. Examples of a heterocyclic groupwherein 2 ring atoms are substituted with oxo (═O) moieties arepyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groupsherein are optionally substituted independently with one or moresubstituents described herein.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings, and includes fused ring systems (at least one ofwhich is aromatic) of 5-20 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, e.g., 2-hydroxypyridinyl),imidazolyl, imidazopyridinyl, pyrimidinyl (including, e.g.,4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl,thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionallysubstituted independently with one or more substituents describedherein.

The heterocycle or heteroaryl groups may be carbon (carbon-linked), ornitrogen (nitrogen-linked) bonded where such is possible. By way ofexample and not limitation, carbon bonded heterocycles or heteroarylsare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline.

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change ordisorder, such as the development or spread of cancer. For purposes ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of symptoms, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can be measured, e.g., byassessing the time to disease progression (TTP) and/or determining theresponse rate (RR).

The terms “cancer” refers to or describe the physiological condition inmammals that is typically characterized by unregulated cell growth. A“tumor” comprises one or more cancerous cells. Examples of cancerinclude, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma,and leukemia or lymphoid malignancies. More particular examples of suchcancers include squamous cell cancer (e.g., epithelial squamous cellcancer), lung cancer including small-cell lung cancer, non-small celllung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinomaof the lung, cancer of the peritoneum, hepatocellular cancer, gastric orstomach cancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectalcancer, endometrial or uterine carcinoma, salivary gland carcinoma,kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer,hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head andneck cancer.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer, regardless of mechanism of action. Classes ofchemotherapeutic agents include, but are not limited to: alkyatingagents, antimetabolites, spindle poison plant alkaloids,cytoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies,photosensitizers, and kinase inhibitors. Chemotherapeutic agents includecompounds used in “targeted therapy” and conventional chemotherapy.Examples of chemotherapeutic agents include: erlotinib (TARCEVA®,Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU(fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®,Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin(cis-diamine,dichloroplatinum(II), CAS No. 15663-27-1), carboplatin (CASNo. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology,Princeton, N.J.), pemetrexed (ALIMTA®, Eli Lilly), trastuzumab(HERCEPTIN®, Genentech), temozolomide(4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide,CAS No. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine,NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1/2,HPPD, and rapamycin.

More examples of chemotherapeutic agents include: oxaliplatin(ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent(SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin(folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib(TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs),gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11,Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.),vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chloranmbucil, AG1478,AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib(GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa andcyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, calicheamicin gamma1I, calicheamicin omegaI1 (Angew Chem.Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A;bisphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores), aclacinomysins, actinomycin, authramycin,azaserine, bleomycins, cactinomycin, carabicin, caminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin,marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide;edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche);ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid; andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, e.g., tamoxifen (including NOLVADEX®; tamoxifencitrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene,keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate);(ii) aromatase inhibitors that inhibit the enzyme aromatase, whichregulates estrogen production in the adrenal glands, such as, e.g.,4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate),AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR®(vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole;AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a1,3-dioxolane nucleoside cytosine analog); (iv) protein kinaseinhibitors such as MEK inhibitors (WO 2007/044515); (v) lipid kinaseinhibitors; (vi) antisense oligonucleotides, particularly those whichinhibit expression of genes in signaling pathways implicated in aberrantcell proliferation, e.g., PKC-alpha, Raf and H-Ras, such as oblimersen(GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGF expressioninhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii)vaccines such as gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®,and VAXID®; PROLEUKIN® rIL-2; topoisomerase 1 inhibitors such asLURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptablesalts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” aretherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (OMNITARG™, 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), tositumomab (Bexxar, Corixia), and the antibody drugconjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

Humanized monoclonal antibodies with therapeutic potential aschemotherapeutic agents in combination with the PI3K inhibitors of theinvention include: alemtuzumab, apolizumab, aselizumab, atlizumab,bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumabmertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab,daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab,fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab,labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab,motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab,ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab,pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab,sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab,urtoxazumab, and visilizumab.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result e.g. from the oxidation, reduction, hydrolysis,amidation, deamidation, esterification, deesterification, enzymaticcleavage, and the like, of the administered compound. Accordingly, theinvention includes metabolites of compounds of the invention, includingcompounds produced by a process comprising contacting a compound of thisinvention with a mammal for a period of time sufficient to yield ametabolic product thereof.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis(2-hydroxy-3-naphthoate)) salts. A pharmaceuticallyacceptable salt may involve the inclusion of another molecule such as anacetate ion, a succinate ion or other counter ion. The counter ion maybe any organic or inorganic moiety that stabilizes the charge on theparent compound. Furthermore, a pharmaceutically acceptable salt mayhave more than one charged atom in its structure. Instances wheremultiple charged atoms are part of the pharmaceutically acceptable saltcan have multiple counter ions. Hence, a pharmaceutically acceptablesalt can have one or more charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, e.g., treatment of the free base with an inorganic acid, such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,methanesulfonic acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, trifluoroacetic acid, maleic acid, succinicacid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalicacid, glycolic acid, salicylic acid, a pyranosidyl acid, such asglucuronic acid or galacturonic acid, an alpha hydroxy acid, such ascitric acid or tartaric acid, an amino acid, such as aspartic acid orglutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid,a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid,or the like.

If the compound of the invention is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,e.g., treatment of the free acid with an inorganic or organic base, suchas an amine (primary, secondary or tertiary), an alkali metal hydroxideor alkaline earth metal hydroxide, or the like. Illustrative examples ofsuitable salts include, but are not limited to, organic salts derivedfrom amino acids, such as glycine and arginine, ammonia, primary,secondary, and tertiary amines, and cyclic amines, such as piperidine,morpholine and piperazine, and inorganic salts derived from sodium,calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminumand lithium.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine.

The terms “compound of this invention,” and “compounds of the presentinvention” and “compounds of Formula I” include compounds of Formulas Iand stereoisomers, geometric isomers, tautomers, solvates, metabolites,and pharmaceutically acceptable salts and prodrugs thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent hydrates, solvates, and polymorphs of suchcompounds, and mixtures thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent unlabeled forms as well as isotopicallylabeled forms of the compounds. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as, but not limited to 2H(deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S,36Cl, and 125I. Various isotopically labeled compounds of the presentinvention, e.g. those into which radioactive isotopes such as 3H, 13C,and 14C are incorporated. Such isotopically labelled compounds may beuseful in metabolic studies, reaction kinetic studies, detection orimaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. Deuterium labelled or substituted therapeutic compounds of theinvention may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism, and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, e.g.increased in vivo half-life or reduced dosage requirements. An 18Flabeled compound may be useful for PET or SPECT studies. Isotopicallylabeled compounds of this invention and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. Further, substitution with heavier isotopes,particularly deuterium (i.e., 2H or D) may afford certain therapeuticadvantages resulting from greater metabolic stability, e.g. increased invivo half-life or reduced dosage requirements or an improvement intherapeutic index. It is understood that deuterium in this context isregarded as a substituent in the compound of the formula (I). Theconcentration of such a heavier isotope, specifically deuterium, may bedefined by an isotopic enrichment factor. In the compounds of thisinvention any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this inventionany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

Benzoxazepin Compounds

The present invention provides benzoxazepin compounds, andpharmaceutical formulations thereof, which are potentially useful in thetreatment of diseases, conditions and/or disorders modulated by PI3kinases. More specifically, the present invention provides compounds ofFormula I:

stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein:

Z¹ is CR¹ or N;

Z² is CR² or N;

Z³ is CR³ or N;

Z⁴ is CR⁴ or N;

B is a pyrazolyl, imidazolyl, or triazolyl ring fused to the benzoxepinring and selected from the structures:

R¹, R², R³, and R⁴ are independently selected from H, F, Cl, Br, I, —CN,—COR¹⁰, —CO₂R¹⁰, —C(═O)N(R¹⁰)OR¹¹, —C(═NR¹⁰)NR¹⁰R¹¹, —C(═O)NR¹⁰R¹¹,—NO₂, —NR¹⁰R¹¹, —NR¹²C(═O)R¹⁰, —NR¹²C(═O)OR¹¹, —NR¹²C(═O)NR¹⁰R¹¹,—NR¹²C(═O)(C₁-C₁₂ alkylene)NR¹⁰R¹¹, —NR¹²(C₁-C₁₂ alkylene)NR¹⁰R¹¹,—NR¹²(C₁-C₁₂ alkylene)OR¹⁰, —NR¹²(C₁-C₁₂ alkylene)C(═O)NR¹⁰R¹¹, —OR¹⁰,—SR¹⁰, —S(O)₂R¹⁰,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰R¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰C(═O)OR¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰C(═O)R¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)R¹⁰,

C₁-C₁₂ alkyl,

C₂-C₈ alkenyl,

C₂-C₈ alkynyl,

C₃-C₁₂ carbocyclyl,

C₂-C₂₀ heterocyclyl,

C₆-C₂₀ aryl,

C₁-C₂₀ heteroaryl,

—(C₃-C₁₂ carbocyclyl)-(C₁-C₁₂ alkyl),

—(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl),

—(C₆-C₂₀ aryl)-(C₁-C₁₂ alkyl),

—(C₁-C₂₀ heteroaryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₃-C₁₂ carbocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₃-C₁₂ carbocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-C(═O)—(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₆-C₂₀ aryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-C(═O)—(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)C(═O)OR¹⁰,

—(C₁-C₁₂ alkylene)C(═O)NR¹⁰R¹¹,

—(C₁-C₁₂ alkylene)-NR¹⁰R¹¹,

—(C₁-C₁₂ alkylene)NR¹²C(═O)R¹⁰,

—(C₁-C₁₂ alkylene)OR¹⁰,

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-NHC(═O)—(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-NR¹⁰R¹¹, and

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl)-NR¹⁰R¹¹,

where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl,aryl, and heteroaryl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, R¹⁰, —SR¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —NR¹⁰R¹¹, —NR¹²C(O)R¹⁰, —CO₂R¹⁰, —C(O)R¹⁰, —CONR¹⁰R¹¹,oxo, and —OR¹⁰;

A is selected from —C(═O)NR⁵R⁶, —NR⁵R⁶, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyland C₁-C₂₀ heteroaryl wherein aryl, heterocyclyl and heteroaryl areoptionally substituted with one or more groups independently selectedfrom F, Cl, Br, I, —CN, —COR¹⁰, —CO₂R¹⁰, —C(═O)N(R¹⁰)OR¹¹,—C(═NR¹⁰)NR¹⁰R¹¹, —C(═O)NR¹⁰R¹¹, —NO₂, —NR¹⁰R¹¹, —NR¹²C(═O)R¹⁰,—NR¹²C(═O)OR¹¹, —NR^(C)(═O)NR¹⁰R¹¹, —NR¹²C(═O)(C₁-C₁₂ alkylene)NR¹⁰R¹¹,—NR¹²(C₁-C₁₂ alkylene)NR¹⁰R¹¹, NR¹²(C₁-C₁₂ alkylene)OR¹⁰, —NR(C₁-C₁₂alkylene)C(═O)NR¹⁰R¹¹, —OR¹⁰, —S(O)₂R¹⁰,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰R¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰C(═O)OR¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰C(═O)R¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)R¹⁰,

C₁-C₁₂ alkyl,

C₂-C₈ alkenyl,

C₂-C₈ alkynyl,

C₃-C₁₂ carbocyclyl,

C₂-C₂₀ heterocyclyl,

C₆-C₂₀ aryl,

C₁-C₂₀ heteroaryl,

—(C₃-C₁₂ carbocyclyl)-(C₁-C₁₂ alkyl),

—(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl),

—(C₆-C₂₀ aryl)-(C₁-C₁₂ alkyl),

—(C₁-C₂₀ heteroaryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₃-C₁₂ carbocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₃-C₁₂ carbocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-C(═O)—(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₆-C₂₀ aryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-C(═O)—(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)C(═O)OR¹⁰,

—(C₁-C₁₂ alkylene)-NR¹⁰R¹¹,

—(C₁-C₁₂ alkylene)NR¹²C(═O)R¹⁰,

—(C₁-C₁₂ alkylene)OR¹⁰,

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-NHC(═O)—(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-NR¹⁰R¹¹, and

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl)-NR¹⁰R¹¹,

where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl,aryl, and heteroaryl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, R¹⁰, —SR¹⁰, —S(O)₂R¹⁰,—NR¹⁰R¹¹, —NR¹²C(O)R¹⁰, —CO₂R¹⁰, —C(O)R¹⁰, —CONR¹⁰R¹¹, and —OR¹⁰;

R⁵ is selected from H, and C₁-C₁₂ alkyl, optionally substituted with oneor more groups independently selected from F, Cl, Br, I, —CN, —CO₂H,—CONH₂, —CONHCH₃, —NH₂, —NO₂, —N(CH₃)₂, —NHCOCH₃, —NHS(O)₂CH₃, —OH,—OCH₃, —OCH₂CH₃, —S(O)₂NH₂, and —S(O)₂CH₃;

R⁶ is selected from C₁-C₁₂ alkyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₁-C₂₀ heteroaryl, and C₆-C₂₀ aryl, each optionallysubstituted with one or more groups independently selected from F, Cl,Br, I, —CH₃, —CH₂OH, —CH₂C₆H₅, —CN, —CF₃, —CO₂H, —C(O)CH₃, —NH₂, —NO₂,—N(CH₃)₂, —NHCOCH₃, —NHS(O)₂CH₃, —OH, oxo, —OCH₃, —OCH₂CH₃, —S(O)₂NH₂,—S(O)₂CH₃, —C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰R¹¹, phenyl, pyridinyl,tetrahydro-furan-2-yl, 2,3-dihydro-benzofuran-2-yl,1-isopropyl-pyrrolidin-3-ylmethyl, morpholin-4-yl, piperidin-1-yl,piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, —C≡CR¹³,—CH═CHR¹³, and —C(═O)NR¹⁰R¹¹;

or R⁵ and R⁶ together with the nitrogen atom to which they are attachedform C₂-C₂₀ heterocyclyl or C₁-C₂₀ heteroaryl, optionally substitutedwith one or more groups selected from F, Cl, Br, I, CH₃, C(CH₃)₃,—CH₂OH, —CH₂CH₂OH, —CH₂C₆H₅, pyridin-2-yl, 6-methyl-pyridin-2-yl,pyridin-4-yl, pyridin-3-yl, pyrimidin-2-yl, pyrazin-2-yl,tetrahydro-furan-carbonyl, 2-methoxy-phenyl, benzoyl, cyclopropylmethyl,(tetrahydrofuran-2-yl)methyl, 2,6-dimethyl-morpholin-4-yl,4-methyl-piperazine-carbonyl, pyrrolidine-1-carbonyl,cyclopropanecarbonyl, 2,4-difluoro-phenyl, pyridin-2-ylmethyl,morpholin-4-yl, —CN, —CF₃, —CO₂H, —CONH₂, —CONHCH₃, —CON(CH₃)₂, —COCF₃,—COCH₃, —COCH(CH₃)₂, —NO₂, NHCH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —NHCOCH₃,—NCH₃COCH₃, —NHS(O)₂CH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OCH₃, —CH₂CH₂OCH₃,—CH₂S(O)₂NHCH₃, —CH₂S(O)₂CH₂CH₃, —S(O)₂NHCH₃, —S(O)₂CH₂CH₃, —S(O)₂NH₂,—S(O)₂N(CH₃)₂ and —S(O)₂CH₃;

R¹⁰, R¹¹ and R¹² are independently selected from H, C₁-C₁₂ alkyl,—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl), —(C₁-C₁₂ alkylene)-(C₆-C₂₀aryl), —(C₁-C₁₂ alkylene)-(C₃-C₁₂ carbocyclyl), C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl, each of which are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —C(CH₃)₂OH, —CH₂C(CH₃)₂OH,—CH₂CH(CH₃)OH, —CH₂CO₂H, —CH₂CO₂CH₃, —CH₂NH₂, —(CH₂)₂N(CH₃)₂, —CH₂C₆H₅,—CN, —CF₃, —CO₂H, —C(O)CH₃, —C(O)CH(OH)CH₃, —CO₂CH₃, —CONH₂, —CONHCH₃,—CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NO₂, —N(CH₃)₂, —N(CH₃)C(CH₃)₂CONH₂,—N(CH₃)CH₂CH₂S(O)₂CH₃, —NHCOCH₃, —NHS(O)₂CH₃, ═O (oxo), —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OH, —OP(O)(OH)₂, —SCH₃, —S(O)₂CH₃, —S(O)₂NH₂,—S(O)₂N(CH₃)₂, —CH₂S(O)₂NHCH₃, —CH₂S(O)₂CH₂CH₃, —S(O)₂NHCH₃,—S(O)₂CH₂CH₃, Pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, cyclopropyl,cyclopentyl, oxetanyl, 4-methylpiperazin-1-yl, and 4-morpholinyl;

or R¹⁰ and R¹¹ together with the nitrogen atom to which they areattached form a C₂-C₂₀ heterocyclyl ring or C₁-C₂₀ heteroaryl each ofwhich are optionally substituted with one or more groups independentlyselected from F, Cl, Br, I, —CH₃, —CH₂OH, —CH₂C₆H₅, —CN, —CF₃, —CO₂H,—CONH₂, —CONHCH₃, —NO₂, —N(CH₃)₂, —NHCOCH₃, —NHS(O)₂CH₃, —OH, oxo,—OCH₃, —OCH₂CH₃, —S(O)₂NH₂, —S(O)₂CH₃, —CH(CH₃)₂, —CH₂CF₃, —CH₂CH₂OH and—C(CH₃)₂OH; and

R¹³ is selected from H, F, Cl, Br, I, —CH₃, —CH₂CH₃, —CN, —CF₃,—CH₂N(CH₃)₂, —CH₂OH, —CO₂H, —CONH₂, —CON(CH₃)₂, —NO₂, and —S(O)₂CH₃.

Exemplary embodiments include Formula Ia compounds wherein B is:

and has the structure:

Exemplary embodiments include Formula Ib compounds wherein B is:

and has the structure:

Exemplary embodiments include Formula Ic compounds wherein B is:

and has the structure:

Exemplary embodiments include Formula Id compounds wherein B is:

and has the structure:

Exemplary embodiments include Formula Ie compounds wherein B is:

and has the structure:

Exemplary embodiments include Formula If compounds wherein B is:

and has the structure:

Exemplary embodiments include Formula Ig compounds wherein B is:

and has the structure:

Exemplary embodiments of Formula I compounds include wherein Z¹ is CR¹;Z² is CR²; Z³ is CR³; and Z⁴ is CR⁴.

Exemplary embodiments of Formula I compounds include wherein Z¹ is N; Z²is CR²; Z³ is CR³; and Z⁴ is CR⁴.

Exemplary embodiments of Formula I compounds include wherein Z¹ is CR¹;Z² is N; Z³ is CR³; and Z⁴ is CR⁴.

Exemplary embodiments of Formula I compounds include wherein Z¹ is CR¹;Z² is CR²; Z³ is N; and Z⁴ is CR⁴.

Exemplary embodiments of Formula I compounds include wherein Z¹ is CR¹;Z² is CR²; Z³ is CR³; and Z⁴ is N.

Exemplary embodiments include Formula Ih compounds:

Exemplary embodiments include Formula Ii compounds:

Exemplary embodiments include Formula Ij compounds:

Exemplary embodiments include wherein R¹, R², R³ and R⁴ areindependently selected from H, F, Cl, Br, I, CN, NO₂, and C₁-C₆ alkyl.

Exemplary embodiments include wherein R² and R³ are independentlyselected from —NR¹⁰R¹¹, —C(═O)NR¹⁰R¹¹ and —(C₁-C₁₂alkylene)C(═O)NR¹⁰R¹¹.

Exemplary embodiments include wherein R² and R³ are independentlyselected from optionally substituted C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀ heteroaryl.

Exemplary embodiments include wherein R² and R³ are independentlyselected from optionally substituted azabicyclo[3.2.1]octanyl,azetidinyl, cyclopropyl, 3,8-diazabicyclo[3.2.1]octanyl,dihydropyrrolidinyl, imidazolyl, morpholinyl, oxetanyl, phenyl,piperazinone, piperazinyl, piperidyl, pyrazinyl, pyrazolyl, pyridinyl,pyridinone, pyrimidinyl, pyrrolidinyl, tetrahydropyranyl, andtetrahydropyridinyl.

Exemplary embodiments include wherein R² and R³ are independently —OR¹⁰.

Exemplary embodiments include wherein R² is —OR¹⁰ and Z³ is N.

Exemplary embodiments include wherein A is —C(═O)NR⁵R⁶.

Exemplary embodiments include wherein R⁵ is CH₃.

Exemplary embodiments include wherein R⁶ is phenyl substituted with oneor more groups independently selected from F, Cl, Br, I, —CH₂OH,—CH₂C₆H₅, —CN, —CF₃, —CO₂H, —CONH₂, —CONHCH₃, —NO₂, —N(CH₃)₂, —NHCOCH₃,—NHS(O)₂CH₃, —OH, —OCH₃, —OCH₂CH₃, —S(O)₂NH₂, —S(O)₂CH₃, morpholin-4-yl,piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, —C≡CR¹³,and —CH═CHR¹³.

Exemplary embodiments include wherein R⁵ and R⁶ together with thenitrogen atom to which they are attached form morpholin-4-yl,piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl,azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl,[1,4]diazepan-1-yl, or indolinyl.

Exemplary embodiments include wherein A is C₂-C₂₀ heterocyclyl or C₁-C₂₀heteroaryl substituted with —CH₂OH, —CH₂CO₂H, —CH(CH₃)CH₂OCH₃, —CH₃,—CH(CH₃)₂₅—CH₂CH(CH₃)₂, —CH₂CF₃, —C(═O)CH₃, —C(═O)NHCH₃, —C(═O)N(CH₃)₂,—CO₂H, —CO₂CH₃, —CH₂CO₂CH₃, —NH₂, —NHC(═O)CH₃, —OH, —OCH₃, —S(O)₂CH₃,1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, 4-morpholinyl,(4-methylpiperazin-1 yl)carboxamide, —CH₂(1H-1,2,4-triazol-5-yl),cyclopropyl, cyclopropylmethyl, or cyclobutyl.

Exemplary embodiments include wherein A is a C₁-C₂₀ heteroaryl selectedfrom pyridyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl,1,3,4-oxadiazol-2(3H)-one, furanyl, thienyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,4-triazol-5(4H)-one,4,5-dihydro-1,2,4-triazin-6(1H)-one, tetrazolyl,pyrrolo[2,3-b]pyridinyl, indazolyl, 3,4-dihydroquinolinyl, andbenzo[d]thiazole.

Exemplary embodiments include wherein A is selected from the structures:

where R⁹ is independently selected from H, F, Cl, Br, I, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂CO₂H, —CH(CH₃)CH₂OCH₃,—CN, —CF₃, —CH₂CF₃, —CH₂NH₂, —CH₂CH₂NH₂, —C(═O)CH₃, —CH₂C(═O)NHCH₃,—C(═O)NHCH₃, —CO₂H, —CH₂CO₂CH₃, —NH₂, —OH, —OCH₃, —SCH₃, —S(O)₂CH₃,cyclopropyl, cyclopropylmethyl, 1-methylpiperid-4-yl,4-methylpiperazin-1-yl, 4-morpholinyl, morpholin-4-yl-ethyl, benzyl, andphenyl, where benzyl and phenyl are optionally substituted with one ormore groups selected from F, Cl, Br, I, —CH₂OH, —CH₂CO₂H, —CN, —CH₂NH₂,—CH₃, —C(═O)CH₃, —C(═O)NHCH₃, —CO₂H, —CH₂CO₂CH₃, —NH₂, —OCH₃, —S(O)₂CH₃,1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, and 4-morpholinyl; andwhere the wavy line indicates the site of attachment.

Exemplary embodiments include wherein A is selected from the structures:

where the wavy line indicates the site of attachment.

Biological Evaluation

Determination of the PI3 kinase activity of a Formula I compound ispossible by a number of direct and indirect detection methods. Certainexemplary compounds described herein were assayed for their p110α(alpha), and other isoform, PI3K binding activity (Example 901) and invitro activity against tumor cells (Example 902). Certain exemplarycompounds of the invention had PI3K binding activity IC50 values lessthan 10 nM. Certain compounds of the invention had tumor cell-basedactivity EC50 values less than 100 nM.

The cytotoxic or cytostatic activity of Formula I exemplary compoundswas measured by: establishing a proliferating mammalian tumor cell linein a cell culture medium, adding a Formula I compound, culturing thecells for a period from about 6 hours to about 5 days; and measuringcell viability (Example 902). Cell-based in vitro assays were used tomeasure viability, i.e. proliferation (IC50), cytotoxicity (EC50), andinduction of apoptosis (caspase activation).

The in vitro potency of Formula I exemplary compounds was measured bythe cell proliferation assay, CellTiter-Glo® Luminescent Cell ViabilityAssay, commercially available from Promega Corp., Madison, Wis. (Example902). This homogeneous assay method is based on the recombinantexpression of Coleoptera luciferase (U.S. Pat. Nos. 5,583,024;5,674,713; 5,700,670) and determines the number of viable cells inculture based on quantitation of the ATP present, an indicator ofmetabolically active cells (Crouch et al (1993) J. Immunol. Meth.160:81-88; U.S. Pat. No. 6,602,677). The CellTiter-Glo® Assay wasconducted in 96 or 384 well format, making it amenable to automatedhigh-throughput screening (HTS) (Cree et al (1995) AntiCancer Drugs6:398-404). The homogeneous assay procedure involves adding the singlereagent (CellTiter-Glo® Reagent) directly to cells cultured inserum-supplemented medium. Cell washing, removal of medium and multiplepipetting steps are not required. The system detects as few as 15cells/well in a 384-well format in 10 minutes after adding reagent andmixing.

The homogeneous “add-mix-measure” format results in cell lysis andgeneration of a luminescent signal proportional to the amount of ATPpresent. The amount of ATP is directly proportional to the number ofcells present in culture. The CellTiter-Glo® Assay generates a“glow-type” luminescent signal, produced by the luciferase reaction,which has a half-life generally greater than five hours, depending oncell type and medium used. Viable cells are reflected in relativeluminescence units (RLU). The substrate, Beetle Luciferin, isoxidatively decarboxylated by recombinant firefly luciferase withconcomitant conversion of ATP to AMP and generation of photons. Theextended half-life eliminates the need to use reagent injectors andprovides flexibility for continuous or batch mode processing of multipleplates. This cell proliferation assay can be used with various multiwellformats, e.g. 96 or 384 well format. Data can be recorded by luminometeror CCD camera imaging device. The luminescence output is presented asrelative light units (RLU), measured over time.

The anti-proliferative effects of Formula I exemplary compounds weremeasured by the CellTiter-Glo® Assay (Example 902) against several tumorcell lines. Potency EC50 values were established for the testedcompounds. The range of in vitro cell potency activities was about 100nM to about 10 μM. Certain tested compounds had EC50 values of less than1 micromolar (1 μM) in stopping proliferation of certain tumor celllines.

Certain ADME properties were measured for certain exemplary compounds byassays including: Caco-2 Permeability (Example 903), HepatocyteClearance (Example 904), Cytochrome P450 Inhibition (Example 905),Cytochrome P450 Induction (Example 906), Plasma Protein Binding (Example907), and hERG channel blockage (Example 908).

Certain exemplary compounds were tested for efficacy by a doseescalation studies by administration in tumor xenograft Taconic nudemouse models (Example 909). The breast cancer cell line MDA-MB-361.1mouse model was administered certain exemplary Formula I compounds alongwith Vehicle (MCT, negative control). The tumor growth delay wasmeasured when dosed orally daily for 21 days at 50 and 100 mg/kg. Bodyweight change over the course of treatment was measured as an indicatorof safety. Treatment of the MDA-MB-361.1 mouse model with certainexemplary Formula I compounds caused tumor growth stasis, inhibition, orregression when dosed orally daily for 21 days.

Exemplary Formula I compounds No. 101-294 in Table 1, No. 295-533 inTable 2, and No. 534-570 in Table 3 were made, characterized, and testedfor inhibition of PI3K alpha (IC₅₀ or K_(i) binding to p110 alpha lessthan 1 micromolar, μM) and selectivity according to the methods of thisinvention, and have the following structures and corresponding names(ChemDraw Ultra, Version 9.0.1, CambridgeSoft Corp., Cambridge Mass.).For example, compound 101 had an IC₅₀ of 0.77 micromole; compound 102had an IC₅₀ of 0.0030 micromole; compound 103 had an IC₅₀ of 0.058micromole; compound 154 had an IC₅₀ of 0.00091 micromole; compound 170had an IC₅₀ of 0.022 micromole; compound 171 had an IC₅₀ of 0.00066micromole; compound 180 had an IC₅₀ of 0.00018 micromole; compound 196had an IC₅₀ of 0.00050 micromole; compound 200 had an IC₅₀ of 0.0020micromole; compound 248 had an IC₅₀ of 0.00037 micromole; compound 251had an IC₅₀ of 0.0014 micromole; compound 253 had an IC₅₀ of 0.0044micromole; compound 280 had an IC₅₀ of 0.20 micromole; compound 338 hadan IC₅₀ of 0.00032 micromole; compound 436 had a K_(i) of 0.00024micromole; and compound 520 had a K_(i) of 0.0021 micromole.

TABLE 1 No. Structure Name 101

N-(2,4-difluorophenyl)-N-methyl- 4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide 102

2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-10-carboxamide 103

2-(1-(2,4-difluorophenyl)-1H-1,2,4- triazol-5-yl)-8-bromo-4,5-dihydrobenzo-2H-oxepino[4,5- d]pyrazole 104

2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carboxamide 105

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-8-(pyrazol-4-yl)-4,5-dihydrobenzo-2H-oxepino[4,5- d]pyrazole 106

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-8-bromo-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole 107

2-(1-(2,4-difluorophenyl)-1H-1,2,4- triazol-5-yl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole-8- carboxamide 108

2-(4-isopropyl-4H-1,2,4-triazol-5- yl)-9-(pyrazol-4yl)-4,5-dihydrobenzo-2H-oxepino[4,5- d]pyrazole 109

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide 110

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-N-methyl-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole-9- carboxamide 111

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-N-(2-hydroxyethyl)-4,5-dihydrobenzo-2H-oxepino[4,5- d]pyrazole-9-carboxamide 112

(2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)(S- dioxothiomorpholino)methanone 113

(4-(2-hydroxypropan-2- yl)piperidin-1-yl)(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone 114

9-(1-isopropyl-1H-pyrazol-5-yl)- 6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3- carboxamide 115

2-(1-isopropyl-1H-pyrazol-5-yl)- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide 116

N-(2-hydroxy-2-methylpropyl)-2- (1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepine-9-carboxamide 117

(2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)(S-dioxothiomorpholino)methanone 118

(4-hydroxypiperidin-1-yl)(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)methanone 119

N-(2-(methylsulfonyl)ethyl)-2-(1- (2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide 120

(4-isopropylpiperazin-1-yl)(2-(1- (2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone 121

N-(1-hydroxy-2-methylpropan-2- yl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide 122

(4-(2-hydroxyethyl)piperazin-1- yl)(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone 123

morpholino(2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-10-yl)methanone 124

(2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)(4-(2,2,2-trifluoroethyl)piperiazin-1- yl)methanone 125

N-(1-(2-hydroxyethyl)-1H-pyrazol- 4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5- dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-9-carboxamide 126

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-N-(isoxazol-3-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepine-9-carboxamide 127

N-(1H-pyrazol-4-yl)-2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-4,5- dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepine-9-carboxamide 128

2-(4-((2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)methyl)piperazin-1-yl)ethanol 129

(4-hydroxypiperidin-1-yl)(2-(1- (2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone 130

9-(piperidin-4-yl)-2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-4,5- dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepine 131

N-((2-(1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxzepin-9- yl)methyl)pyrazin-2-amine132

2-hydroxy-1-(4-((2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)methyl)piperazin-1-yl)ethanone 133

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-N-(2-(methylsulfonyl)ethyl)-5,6-dihydrobenzo[b]imidazo[1,2- d][1,4]oxezepine-9-carboxamide 134

2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-N-(2-(methylsulfonyl)ethyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide 135

2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide 136

(2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-10-yl)(4-isopropylpiperazin-1-yl)methanone 137

2-(1-(2,4-difluorophenyl)-1H-1,2,4- triazol-5-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide 138

2-(4-cyano-1-isopropyl-1H- pyrazol-5-yl)-5,6- dihydrobenzo[f]imidzo[1,2-d][1,4]oxazepine-9-carboxamide 139

2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carboxamide 140

N-(2-hydroxyethyl)-N-isopropyl- 4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide 141

4-((2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)methyl)piperazin-2-one 142

2-(4-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)piperidin-1-yl)ethanol 143

2-(4-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide 144

9-(azetidin-3-yl)-2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepine 145

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(piperazine-1-carbonyl)-4,5-dihydrobenzo-2H-oxepino[4,5- d]pyrazole 146

2-(4-isopropyl-4H-1,2,4-triazol-5- yl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole 147

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4,5-dihydrobenzo- 2H-oxepino[4,5-d]pyrazole-9- carboxamide148

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(1-(methylsulfonyl)azetidin-3-yl)-4,5- dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepine 149

1-(3-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)azetidin-1-yl)ethanone 150

2-hydroxy-1-(3-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)azetidin-1-yl)ethanone 151

2-hydoxy-1-(4-(2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5- yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)piperidin-1-yl)ethanone 152

9-(1-(2- (methylsulfonyl)ethyl)piperidin-4-yl)-2-(1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepine 153

((3S,5R)-3,5-dimethylpiperazin-1- yl)(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone 154

2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-9-piperid-4-yl-4,5-dihydrobenzo-2H-oxepino[4,5- d]pyrazole 155

2-(3-(2-isopropyl-1H-1,2,4- triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)azetidin-1-yl)acetamide 156

N-(azetidin-3-yl)-2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepine-9-carboxamide 157

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(1-(2-(methylsulfonyl)ethyl)azetidin-3- yl)-4,5- dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine 158

N-methyl-2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carboxamide 159

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carboxamide 160

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-10-(1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 161

2-(1-(2-chlorophenyl)-1H- imidazol-2-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide 162

(2-(1-(2,4-difluorophenyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-10-yl)(4-(2-hydroxyethyl)piperazin-1- yl)methanone 163

N-(1-hydroxy-2-methylpropan-2- yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carboxamide164

N-(1-hydroxy-2-methylpropan-2- yl)-2-(1-(S-dioxo-tetrahydrothiophen-3-yl)-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-10-carboxamide 165

2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide 166

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(1-(pyridin-4-ylmethyl)azetidin-3-yl)-4,5- dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine 167

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-N-(1-isopropylazetidin-3-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepine-9-carboxamide 168

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-N-methoxy-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carboxamide 169

2-(3-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)azetidin-1- yl)ethanol170

2-(3-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5- d][1,4]oxazepin-9-yl)azetidin-1-yl)-2-methylpropan-1-ol 171

2-(1-(2,4-difluorophenyl)-1H-1,2,4- triazol-5-yl)-8-(1-(2-(methylsulfonyl)ethyl)azetidin-3- yl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole 172

2-(3-{2-[2-(2,4-Difluoro-phenyl)- 2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza- benzo[e]azulen-8-yl}-azetidin-1- yl)-acetamide 173

N-hydroxy-2-(1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carboxamide 174

2-(1-(2,4-difluorophenyl)-1H-1,2,4- triazol-5-yl)-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carboxamide 175

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-[1-(2-methanesulfonyl-ethyl)-piperidin- 4-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene 176

2-{4-[2-(2-Isopropyl-2H- [1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8- yl]-pyrazol-1-yl}-ethanol 177

1-(4-{2-[2-(2,4-Difluoro-phenyl)- 2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza- benzo[e]azulen-9-yl}-piperidin-1-yl)-2-methyl-propan-2-ol 178

2-(4-{2-[2-(2,4-Difluoro-phenyl)- 2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza- benzo[e]azulen-9-yl}-piperidin-1- yl)-acetamide 179

2-(4-{2-[2-(2,4-Difluoro-phenyl)- 2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza- benzo[e]azulen-9-yl}-piperidin-1- yl)-ethanol 180

1-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 181

2-{3-[2-(2-Isopropyl-2H- [1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8- yl]-azetidin-1-yl}-acetamide 182

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol 183

1-(3-{2-[2-(2,4-Difluoro-phenyl)- 2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza- benzo[e]azulen-8-yl}-azetidin-1-yl)-2-methyl-propan-2-ol 184

methyl 2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carboxylate 185

methyl 2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carboxylate 186

2-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol 187

10-bromo-2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 188

[4-{2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9- yl}-1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-methanol 189

2-(4-{2-[2-(2,4-Difluoro-phenyl)- 2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza- benzo[e]azulen-9-yl}-piperidin-1-yl)-2-methyl-propan-1-ol 190

1-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 191

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(1-(2-(methylsulfonyl)ethyl)azetidin-3- yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 192

2-(3-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)azetidin-1-yl)acetamide 193

(1-aminocyclopropyl)(3-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)azetidin-1-yl)methanone 194

9-bromo-2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 195

1-(4-(2-(1-isopropyl-4-methyl-1H- imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 196

2-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide 197

2-(3-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)azetidin-1-yl)-N,N-dimethylethanesulfonamide 198

2-(3-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)azetidin-1-yl)-N,N-dimethylacetamide 199

9-(4,4-dimethyl-4,5-dihydrooxazol- 2-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 200

N-isopropyl-2-(3-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)azetidin-1-yl)acetamide 201

2-(3-{2-[2-(2,4-Difluoro-phenyl)- 2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza- benzo[e]azulen-8-yl}-azetidin-1- yl)-ethanol 202

1-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol 203

3-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-10-yl)pyridin- 2(1H)-one 204

9-(1-(2-(3-fluoroazetidin-1- yl)ethylsulfonyl)azetidin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 205

2-(3-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)azetidin-1-yl)-2-methylpropanamide 206

2-(4-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol 207

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)ethanol 208

2-(5-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)ethanol 209

2-(1-(2-morpholinoethyl)-1H- imidazol-2-yl)-10-(1H-pyrazol-4- yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 210

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-9-(1-(2-morpholinoethyl)-1H-pyrazol-4- yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 211

2-(4-(2-(3-amino-1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol 212

2-(3-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)azetidin-1-yl)-N-methylacetamide 213

1-(4-(2-(3-amino-1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 214

1-(4-(2-(1-isopropyl-1H-imidazol- 2-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol- 1-yl)-2-methylpropan-2-ol 215

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide 216

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid 217

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 218

3-(2-(1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-10-yl)pyridin- 2(1H)-one 219

5-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)pyridin-2- amine 220

2-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)ethanol 221

2-(2-(9-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-2-yl)-1H-imidazol-1-yl)-N-methylacetamide 222

N,N-diethyl-2-(4-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanamine 223

5-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)pyrimidin-2- amine 224

9-(1H-imidazol-5-yl)-2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 225

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(1-(2-(methylsulfonyl)ethyl)piperidin-4- yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 226

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide 227

2-hydroxy-1-(4-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropan-1-one 228

(2S)-2-hydroxy-1-(3-(4-(2-(1- isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol- 1-yl)azetidin-1-yl)propan-1-one 229

2-(4-(2-(3-amino-1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)ethanol 230

2-(3-(4-(2-(1-isopropyl-3-methyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanol 231

5-(5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine 232

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 233

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine 234

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-10-(4-methylpiperazin-1-yl)-5,6-dihydroimidazo[1,2-d] pyrido[4,3-f][1,4]oxazepine 235

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-9-(pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 236

9-(5-fluoropyridin-3-yl)-2-(1- isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 237

2-(3-amino-1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carbonitrile 238

N-(5-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)pyridin-2- yl)acetamide239

9-chloro-2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5- d][1,4]oxazepine 240

9-bromo-2-(1-isopropyl-3- (methylthio)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 241

5-(9-(5-fluoropyridin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl- 1H-1,2,4-triazol-3-amine 242

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine243

3-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide 244

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-9-(pyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 245

5-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-N,N-dimethylpyrimidin-2-amine 246

5-(5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-2-yl)-1-isopropyl-N-methyl-1H-1,2,4-triazol-3-amine 247

N-isopropyl-2-(4-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide 248

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,2-dimethylpropanamide 249

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1- yl)-N,N-dimethylethanesulfonamide 250

2-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide 251

2-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid 252

1-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol 253

5-(9-fluoro-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl- 1H-1,2,4-triazol-3-amine 254

2-(4-(2-(3-methyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol 255

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-2-methyl-1H-imidazol-1-yl)ethanol 256

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H- imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 257

5-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)pyrimidin-2- amine 258

5-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-10-yl)pyridin- 2(1H)-one 259260 261

N-(azetidin-3-yl)-2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3- f][1,4]oxazepin-10-amine 262

3-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10- ylamino)propane-1,2-diol 263

3-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-10-yl)pyridine- 2(1H)-one264 265

1-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-2-methyl-1H-imidazol-1-yl)-2-methylpropan- 2-ol 266 267 268 269

3-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d][4,3-f][1,4]oxazepin-10- yl)pyridin-2(1H)-one 270

2-(5-(9-cyclopropyl-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-3-methyl- 1H-1,2,4-triazol-1-yl)propan-1-ol 271

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(2-methyl-1H-imidazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 272

1-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1-methyl-1H-imidazol-2-yl)-2-methylpropan- 2-ol 273

1-(4-(2-(3-(hydroxymethyl)-1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 274

N-tert-butyl-2-(4-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide 275

2-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N-methylacetamide 276

N-ethyl-2-(4-(2-(1-isopropyl-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide 277

N-isopropyl-2-(4-(2-(1-isopropyl- 3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide 278

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide 279

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N-methylacetamide 280

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5- d][1,4]oxazepine 281

10-fluoro-2-(1-isopropyl-3-methyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 282

9-(1,2-dimethyl-1H-imidazol-4-yl)- 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 283

5-(10-fluoro-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl- 1H-1,2,4-triazol-3-amine 284

9,10-difluoro-2-(1-isopropyl-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 285

2-(4-(2-(1,3-dimethyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol 286

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(1-(2-methoxyethyl)piperidin-4-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 287

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropanamide 288

2-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1- yl)ethanol289

2-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropanamide 290

1-(5-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-imidazol-2-yl)-2-methylpropan-2-ol 291

9-(1,2-dimethyl-1H-imidazol-5-yl)- 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 292

1-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropan-2-ol 293

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1- yl)ethanol294

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine

TABLE 2 No. Structure Name 295

methyl 2-(2-ethoxyphenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate 296

methyl 2-(3-isopropylphenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazpine-9-carboxylate 297

methyl 2-(2-ethylphenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate 298

methyl 2-(2-isopropylphenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate 299

methyl 2-(3- (trifluoromethyl)phenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate 300

2-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)acetamide 301

2-(5-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-2-methyl-1H-imidazol-2-yl)ethanol 302

1-(4-(2-(1-isopropyl-3- (methoxymethyl)-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 303

(3R,4R)-4-(2-(1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-3- ol 304

racemic-trans-2-(3-hydroxy-4-(2- (1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide 305

2-(5-(9-bromo-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl- 1H-1,2,4-triazol-3-yl)acetamide 306

5-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10- yl)pyridin-2(1H)-one 307

4-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10- yl)piperazin-2-one 308

2-(4-(2-(1-isopropyl-3- (methoxymethyl)-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide 309

2-(1-isopropyl-3- (methoxymethyl)-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][l,4]oxazepine 310

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-methoxy-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepine 311

9-fluoro-2-(1-isopropyl-3-methyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 312

5-(9,10-difluoro-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl- 1H-1,2,4-triazol-3-amine 313

9-bromo-2-(3-cyclopropyl-1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 314

9-(1-ethylpiperidin-4-yl)-2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 315

(5-(5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)methanol 316

3-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)propanamide 317

9-chloro-2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepine 318

1-(5-(5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl- 1H-1,2,4-triazol-3-yl)-N,N-dimethylmethanamine 319

racemic-cis-2-(3-hydroxy-4-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide 320

racemic-cis-2-(3-hydroxy-4-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide 321

2-((1R,3r,5S)-3-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-8-azabicyclo[3.2.1]octan-8- yl)acetamide 322

2-((1R,3S,5S)-3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-8- azabicyclo[3.2.1]octan-8- yl)acetamide 323

2-(1-isopropyl-1H-1,2,4-triazo1-5- yl)-9-(4-methylpiperazin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2- f][l,4]oxazepine 324

4-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9- yl)piperazin-2-one 325

4-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9- yl)piperazin-2-one 326 327

4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-10-yl(pyridin- 2(1H)-one 328

(3R,4S)-4-(2-(1-isopropyl-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-3- ol 329

2-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide 330

trans-racemic-2-(3-hydroxy-4-(2- (1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,2-dimethylpropanamide 331

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)piperazin-1-yl)-N,N-dimethylacetamide 332

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)piperazin-1-yl)acetamide 333

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin- 9(8H)-one 334

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2- f][1,4]oxazepin-9-yl)piperazin-1-yl)-N-methylacetamide 335

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2- f][1,4]oxazepin-9-yl)piperazin-1-yl)-N,N-dimethylacetamide 336

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)acetic acid 337

1-((2-(1-isopropyl-1H-pyrazol-5- yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methyl)urea 338

(2S)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 339

1-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9- yl)piperidine-4-carboxamide 340

1-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9- yl)piperidin-4-ol 341

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-morpholino-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepine 342

N-isopropyl-2-(4-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)piperazin-1-yl)acetamide 343

1-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9- yl)azetidine-3-carboxamide 344

(2S)-2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)propanamide 345

(2R)-2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)propanamide 346

2-(1-isopropyl-1H-pyrazol-5-yl)- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide 347

(2-(1-isopropyl-1H-pyrazol-5-yl)- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methanamine 348

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-9-(oxetan-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 349

2-(3-hydroxy-4-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,2-dimethylpropanamide 350

2-(3-hydroxy-4-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl )piperidin-1-yl)-N,2-dimethylpropanamide 351

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)acetamide 352

N-hydroxy-2-(2-(1-isopropyl-1H- l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)acetamide 353

(9-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-2-yl)(S-dioxothiomorpholino)methanone 354

1-((2-(1-(2,4-difluorophenyl)-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)methyl)urea 355

(2-(1-(2,4-difluorophenyl)-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)methanamine 356

9-(1-(2-(dimethylamino)-2- oxoethyl)piperidin-4-yl)-N-(2-hydroxyethyl)-N-isopropyl-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 357

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(1-isopropylpiperidin-4-yl)-5,6-dihydrobenzo[f]imidazo[l,2- d][1,4]oxazepine 358

2-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropan-1-ol 359

2-(4-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropan-1-ol 360

4- (2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)pyrazolidine- 3,5-dione361

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 362

2-(3-hydroxy-4-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide 363

1-((2-(1-(2,4-difluorophenyl)-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)methylamino)-2-methylpropan- 2-ol 364

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 365

(2R)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl(pyrrolidine-2-carboxamide 366

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(pyrrolidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepine 367

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-N-methyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2- f][1,4]oxazepin-9-amine 368

(2S,4R)-4-hydroxy-1-(2-(1- isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl(pyrrolidine-2- carboxamide 369

(2S)-1-(2-(1-isopropyl-3-methyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 370

1-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9- yl)azetidin-3-ol 371

(3R)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)pyrrolidin-3- ol372

(1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)piperidin-4-yl)methanol 373

(2S,4S)-4-fluoro-1-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 374

(2S,4R)-4-hydroxy-1-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 375

(2S)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 376

(2R)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 377

(2S)-1-(2-(1-isopropyl-1H- imidazol-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 378

(2S)-1-(2-(1-(2,4-difluorophenyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 379

(2R)-2-(2-(1-isopropyl-3-methyl 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl(pyrrolidine1-carboxamide 380

(2S)-2-(2-(1-isopropyl-3-methyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)pyrrolidine-1-carboxamide 381

(2S)-4,4-difluoro-1-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 382

(2S,4S)-4-fluoro-1-(2-(1- isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4f][1,4]oxazepin-9-yl)pyrrolidine- carboxamide 383

(2S)-4,4-difluoro-1-(2-(1- isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2- carboxamide 384

(2S,4S)-4-hydroxy-1-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 385

(2S,4S)-4-hydroxy-1-(2-(1- isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2- carboxamide 386

2-(1-isopropyl-1H-imidazol-2-yl)- 5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 387

(5-(9-chloro-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-3-yl(methanol 388

(2R)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)-2,5-dihydro-1H-pyrrole-2-carboxamide 389

(2S)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- t][1,4]oxazepin-9-yl)-2,5-dihydro-1H-pyrrole-2-carboxamide 390

(5-(9-(pyrrolidin-1-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol 391

(2S)-1-(2-(1-(3,5-difluorophenyl)- 3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 392

(2S)-2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4 f][1,4]oxazepin-9- ylamino)propanamide393

(2S)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4 f][1,4]oxazepin-9-yl)-3,3-dimethylpyrrolidine-2- carboxamide 394

(5-(9-(dimethylamino)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-3yl(methanol 395

(2S,3S)-3-hydroxy-1-(2-(1- isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4f][1,4]oxazepin-9-yl)pyrrolidine-2- carboxamide 396

(2S,3R)-3-hydroxy-1-(2-(1- isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4f][1,4]oxazepin-9-yl)pyrrolidine- carboxamide 397

(2S,3R)-3-hydroxy-1-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 398

(2S,3S)-3-hydroxy-1-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 399

(2S)-1-(2-(3-methyl-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 400

(2S,4R)-4-fluoro-1-(2-(1- isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl(pyrrolidine-2- carboxamide 401

(2S,4R)-4-fluoro-1-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 402

(2S)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)-2-methylpyrrolidine-2-carboxamide 403

racemic-cis-1-isopropyl-4-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidine-3-carboxamide 404

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9- ylamino)acetamide 405

(2S)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)-N-methylpyrrolidine-2-carboxamide 406

(2S,3S)-1-(2-(1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)-3-methylpyrrolidine-2-carboxamide 407

(2S,4R)-1-(2-(1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)-4-methoxypyrrolidine-2- carboxamide 408

(2S,3S)-1-(2-(1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)-3-methoxypyrrolidine-2- carboxamide 409

(2S)-1-(2-(1-cyclohexyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 410

(2S)-1-(2-(1-(2-chlorophenyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 411

9-bromo-2-(1-isopropyl-3-methyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 412

ethyl 2-(4-(2-(1-isopropyl-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate 413

(5-(9-(dimethylamino)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-isopropyl- 1H-1,2,4-triazol-3-yl)methanol 414

4-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1-methyl-1,2,5,6-tetrahydropyridine-3- carboxamide 415

4-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1-methyl-1,2,3,6-tetrahydropyridine-3- carboxamide 416

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-N-methyl-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-amine 417

(5-(9-(3,3-difluoroazetidin-1-yl)- 5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)- 1-isopropyl-1H-1,2,4-triazol-3-yl)methanol 418

9-chloro-2-(1-isopropyl-1H- pyrazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepine 419

2-(3-methyl-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-9-(2-(1-methylpiperidin-2- yl)pyrrolidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepine 420

2-(3-methyl-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5- yl)-9-(2-(2-methylbenzyl)pyrrolidin-1-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 421

2-(3-methyl-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-9-(2-(piperidin-1- ylmethyl)pyrrolidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepine 422

2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-N,N-dimethyl-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-amine 423

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-9-(1-methyl-1H-pyrazol-4-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 424

2-(3-amino-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-10-carbonitrile 425

2-(3-amino-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carbonitrile 426

(2S)-2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9- yloxy)propanamide427

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9- yloxy)acetamide 428

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)acetamide 429

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9- yloxy)-2-methylpropanamide 430

(2S,4R)-4-cyano-1-(2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 431

5-(9-cyclopropyl-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl- 1H-1,2,4-triazol-3-amine 432

5-(10-fluoro-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-3-amine 433

(2S)-1-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 434

(2S)-1-(2-(1-isopropyl-1H- pyrazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 435

3-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-2- methylpropanamide436

(2S)-2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)propanamide 437

(3S)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)pyrrolidine-3-carbonitrile 438

N-((1H-pyrazol-5-yl)methyl)-2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9- amine 439

2-(2-(1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-ylamino)propan- 1-ol440

2-(1-isopropyl-3- (methoxymethyl)-1H-1,2,4-triazol- 5-yl)-9-methyl-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 441

N-(3,4-dimethoxybenzyl)-2-(1- (2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine 442

5-(10-cyclopropyl-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-3-amine 443

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-9-carbonitrile 444

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- ylamino)acetamide 445

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yl)ethanesulfonamide 446

(R)-2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9- yloxy)propanamide447

9-(difluoromethyl)-2-(1-isopropyl- 3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 448

4-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1-methyl-1,2,3,6-tetrahydropyridine-3- carboxamide 449

4-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1-methyl-1,2,3,6-tetrahydropyridine-3- carboxamide 450

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9- ylamino)-1-(1-methyl-1H-imidazol-2-yl)ethanol 451

2-(1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-amine 452

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9- yloxy)-3-methylbutanamide 453

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9- amine 454

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-10-(1-methyl-1H-pyrazol-4-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 455

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-10-carbonitrile 456

2-(1-(2,4-difluorophenyl)-1H- 1,2,4-triazol-5-yl)-N-(2-(methylsulfonyl(benzyl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine 457

1-(2-(2-(1-(2,4-difluorophenyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-ylamino)ethyl)pyrrolidin-2-one 458

2-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9- ylamino)acetamide459

1-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidine-2-carboxamide 460

2-((2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-yl)(methyl)amino)acetamide 461

N-(3-(1H-imidazol-1-yl)propyl)-2- (1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine 462

N-((1H-imidazol-2-yl)methyl)-2- (1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine 463

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-amine 464

1-(2,2,2-trifluoroethyl)-5-(10- (trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-amine 465

2-(2-(1-(2,4-difluorophenyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-ylamino)-1-(1-methyl-1H-imidazol-2-yl)ethanol 466

8-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)- 3,8-diazabicyclo[3.2.1]octan-2-one467

3-methyl-2-(2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)butanamide 468

2-(1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-ol 469

(2S)-1-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 470

(2S)-1-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidine-2-carboxamide 471

(3S)-4-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)morpholine-3-carboxamide 472

2-methyl-2-(2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)propanamide 473

(2R)-2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9- ylamino)propanamide474

2-(2-(3-methyl-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9-ylamino)acetamide 475

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(2-(methylsulfonyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 476

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)benzamide 477

9-(2-ethylphenyl )-2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 478

(2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yl)phenyl(methanol 479

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-amine 480

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-amine 481

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-10-methyl-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 482

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-9-methyl-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 483

10-(difluoromethyl)-2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[4,3-f][1,4]oxazepine 484

1-isopropyl-5-(10- (trifluoromethyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4- triazol-3-amine 485

(2R)-2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)propanamide 486

(2S)-2-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)propanamide 487

(2R)-2-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)propanamide 488

N-(3,4-dimethoxybenzyl)-2-(3- methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine 489

2-(3-methyl-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2- d]pyrido[3,4-f][1,4]oxazepin-9- amine 490

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ol 491

2-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9-ylamino)acetic acid492

9-(difluoromethoxy)-2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 493

2-(1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-amine 494

(2S)-2-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)butanamide 495

(2R)-2-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)butanamide 496

2-(2-(1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4- f][1,4]oxazepin-9- ylamino)acetamide497

3-((2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yloxy)methyl)oxetan-3-amine 498

1-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidine-2-carboxamide 499

9-ethyl-2-(1-isopropyl-3-methyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 500

1-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)piperidine-2-carboxamide 501

(2S)-3-methyl-2-(2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)butanamide502

(2R)-3-methyl-2-(2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)butanamide503

ethyl 3-(4-(2-(1-isopropyl-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate 504

methyl 3-(4-(2-(1-isopropyl-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate 505

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-9-(1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 506

3-(4-(2-(1-isopropyl-3-methyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid 507

9-isopropoxy-2-(1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 508

methyl 2-(4-(2-(1-isopropyl-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate 509

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(oxetan-3-yloxy)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 510

9-ethoxy-2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 511

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-(2,2,2-trifluoroethoxy)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 512

(2S)-2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yloxy)propanoic acid 513

(2S)-3-hydroxy-2-(2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yloxy)propanamide 514

(2S)-2-(2-(1-isopropyl-1H- 11580493,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)butanamide 515

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-9-methoxy-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 516

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-9-methoxy-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 517

9-ethoxy-2-(1-isopropyl-3-methyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 518

9-isopropoxy-2-(1-isopropyl-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 519

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-9-(2,2,2-trifluoroethoxy)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 520

2-(1-isopropyl-3-methyl-1H-1,2,4- triazol-5-yl)-9-(oxetan-3-yloxy)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 521

9-cyclopropoxy-2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 522

9-cyclobutoxy-2-(1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 523

9-cyclobutoxy-2-(1-isopropyl-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 524

N-((3-aminooxetan-3-yl)methyl)- 2-(1-isopropyl-1H-1,2,4-triazol-5-yj)-5,6- dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-amine 525

(3-amino-1-(2-(1-isopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)azetidin-3- yl(methanol526

2-(2-(1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- ylamino)acetamide 527

1-(2-(1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yloxy)cyclopropanecarboxamide 528

cis-2-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)cyclopropanecarboxamide 529

(2S)-2-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- ylamino)propanamide 530

trans-2-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)cyclopropanecarboxamide 531

(2S)-3-hydroxy-2-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)propanamide 532

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9- yloxy)pentanamide 533

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yloxy)-4-methylpentanamide

TABLE 3 No. Structure Name 534

9-cyclopropoxy-2-(1-isopropyl-3- methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine 535

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)-3- methylbutanamide 536

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylthio) propanamide 537

2-(2-(1-isopropyl-1H-1,2,4-triazol- 5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylthio) propanamide 538

(2S)-1-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yl)azetidine-2-carboxamide 539

(2S)-2-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin- 9-ylamino)propanamide 540

(2S)-2-(2-(1-methyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9- yloxy)propanamide 541

(2S)-4-hydroxy-2-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2][1,4] oxazepin-9-yloxy)butanamide 542

(2S)-3-methoxy-2-(2-(1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo [1,2-d][1,4]oxazepin-9-ylamino)propanamide 543

(2S)-1-(2-(1-(2,2,2-trifluoroethyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yl)piperazine-2-carboxamide 544

(2S)-2-(2-(1-ethyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yloxy) propanamide 545

(2S)-2-(2-(1-tert-butyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9- yloxy)propanamide 546

(2S)-2-(2-(1-(2,4-difluorophenyl)- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9- yloxy)propanamide 547

(2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methyl carbamate 548

(2S)-1-(2-(3-methyl-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo [1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide 549

2-cyclopropyl-2-(2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yloxy)acetamide 550

(2S)-2-((2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yl)(methyl)amino)propanamide 551

(2S)-1-(2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yl)azetidine-2-carboxamide 552

1-((2-(1-isopropyl-1H-1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yl)methyl)-1- methylurea553

(2S)-1-(2-(3-methyl-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f] imidazo[1,2-d][1,4]oxazepin-9-yl)azetidine-2-carboxamide 554

(2S)-2-(2-(1-cyclopropyl-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yloxy) propanamide 555

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-10-phenyl-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine 556

1-isopropyl-5-(10-phenyl-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4- triazol-3-amine 557

2-(1-isopropyl-1H-1,2,4-triazol-5- yl)-10-(pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine 558

1-isopropyl-5-(10-(pyrimidin-5- yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin- 2-yl)-1H-1,2,4-triazol-3-amine 559

1-(2-chlorophenyl)-5-(10- (pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin- 2-yl)-1H-1,2,4-triazol-3-amine 560

10-(4-chlorophenyl)-2-(1- isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine 561

5-(10-(4-chlorophenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl- 1H-1,2,4-triazol-3-amine 562

10-(4-chlorophenyl)-2-(1-(2- chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo [1,2-d][1,4]oxazepine 563

2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-10-phenyl-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine 564

1-(2-chlorophenyl)-5-(10-phenyl- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4- triazol-3-amine 565

2-(1-(2-chlorophenyl)-1H-1,2,4- triazol-5-yl)-10-(pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine 566

1-(2-chlorophenyl)-5-(10-(4- chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-amine 567

9-(4-chlorophenyl)-2-(1-isopropyl- 1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine 568

9-(4-chlorophenyl)-2-(1-(2- chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo [1,2-d][1,4]oxazepine 569

5-(9-(4-chlorophenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl- 1H-1,2,4-triazol-3-amine 570

1-(2-chlorophenyl)-5-(9-(4- chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-amine

Administration of Formula I Compounds

The Formula I compounds of the invention may be administered by anyroute appropriate to the condition to be treated. Suitable routesinclude oral, parenteral (including subcutaneous, intramuscular,intravenous, intraarterial, intradermal, intrathecal and epidural),transdermal, rectal, nasal, topical (including buccal and sublingual),vaginal, intraperitoneal, intrapulmonary and intranasal. For localimmunosuppressive treatment, the compounds may be administered byintralesional administration, including perfusing or otherwisecontacting the graft with the inhibitor before transplantation. It willbe appreciated that the preferred route may vary with e.g. the conditionof the recipient. Where the compound is administered orally, it may beformulated as a pill, capsule, tablet, etc. with a pharmaceuticallyacceptable carrier or excipient. Where the compound is administeredparenterally, it may be formulated with a pharmaceutically acceptableparenteral vehicle and in a unit dosage injectable form, as detailedbelow.

A dose to treat human patients may range from about 10 mg to about 1000mg of Formula I compound. A typical dose may be about 100 mg to about300 mg of the compound. A dose may be administered once a day (QID),twice per day (BID), or more frequently, depending on thepharmacokinetic and pharmacodynamic properties, including absorption,distribution, metabolism, and excretion of the particular compound. Inaddition, toxicity factors may influence the dosage and administrationregimen. When administered orally, the pill, capsule, or tablet may beingested daily or less frequently for a specified period of time. Theregimen may be repeated for a number of cycles of therapy.

Methods of Treatment with Formula I Compounds

Formula I compounds of the present invention are useful for treatinghyperproliferative diseases, conditions and/or disorders including, butnot limited to, those characterized by over expression of lipid kinases,e.g. PI3 kinase. Accordingly, an aspect of this invention includesmethods of treating or preventing diseases or conditions that can betreated or prevented by inhibiting lipid kinases, including PI3. In oneembodiment, the method comprises administering to a mammal in needthereof a therapeutically effective amount of a compound of Formula I,or a stereoisomer, geometric isomer, tautomer, or pharmaceuticallyacceptable salt thereof. In one embodiment, a human patient is treatedwith a compound of Formula I and a pharmaceutically acceptable carrier,adjuvant, or vehicle, wherein said compound of Formula I is present inan amount to detectably inhibit PI3 kinase activity.

Formula I compounds may also be useful for treating hyperproliferativediseases characterized by over expression of protein kinases such asthose encoded by PIM; the genes Pim-1, Pim-2, and Pim-3 (ProviralInsertion, Moloney) which are implicated in lymphoma and solid-tumordevelopment (Cuypers et al. (1984) Cell, vol. 37 (1) pp. 141-50; Seltenet al. (1985) EMBO J. vol. 4 (7) pp. 1793-8; van der Lugt et al. (1995)EMBO J. vol. 14 (11) pp. 2536-44; Mikkers et al. (2002) Nature Genetics,vol. 32 (1) pp. 153-9; van Lohuizen et al. (1991) Cell, vol. 65 (5) pp.737-52.

Cancers which can be treated according to the methods of this inventioninclude, but are not limited to, breast, ovary, cervix, prostate,testis, genitourinary tract, esophagus, larynx, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoidcarcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC),small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma,pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,Hodgkin's and leukemia.

Formula I compounds may be useful for in vitro, in situ, and in vivodiagnosis or treatment of mammalian cells, organisms, or associatedpathological conditions, such as systemic and local inflammation,immune-inflammatory diseases such as rheumatoid arthritis, immunesuppression, organ transplant rejection, allergies, ulcerative colitis,Crohn's disease, dermatitis, asthma, systemic lupus erythematosus,Sjögren's Syndrome, multiple sclerosis, scleroderma/systemic sclerosis,idiopathic thrombocytopenic purpura (ITP), anti-neutrophil cytoplasmicantibodies (ANCA) vasculitis, chronic obstructive pulmonary disease(COPD), psoriasis, and for general joint protective effects.

Formula I compounds may be useful for treating conditions of the brainand central nervous system which require transport across theblood-brain barrier. Certain Formula I compounds have favorablepenetrant properties for delivery to the brain. Disorders of the brainwhich may be effectively treated with Formula I compounds includemetastatic and primary brain tumors, such as glioblastoma and melanoma.

Formula I compounds may be useful for treating ocular disorders such aswet and dry Age-related Macular Degeneration (AMD) and retina edema, bylocalized delivery to the eye. Certain Formula I compounds havefavorable properties for delivery to, and uptake into, the eye. CertainFormula I compounds may enhance efficacy and extend duration of responsefor treatment of wet AMD in combination with ranibizumab (LUCENTIS®,Genentech, Inc.) and bevacizumab (AVASTIN®, Genentech, Inc.).

Another aspect of this invention provides a compound of this inventionfor use in the treatment of the diseases or conditions described hereinin a mammal, e.g., a human, suffering from such disease or condition.Also provided is the use of a compound of this invention in thepreparation of a medicament for the treatment of the diseases andconditions described herein in a warm-blooded animal, such as a mammal,e.g. a human, suffering from such disorder.

Pharmaceutical Formulations

In order to use a Formula I compound for the therapeutic treatment(including prophylactic treatment) of mammals including humans, it isnormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition. According to this aspect of theinvention there is provided a pharmaceutical composition comprising acompound of this invention in association with a pharmaceuticallyacceptable diluent or carrier.

A typical formulation is prepared by mixing a Formula I compound and acarrier, diluent or excipient. Suitable carriers, diluents andexcipients are well known to those skilled in the art and includematerials such as carbohydrates, waxes, water soluble and/or swellablepolymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents,water and the like. The particular carrier, diluent or excipient usedwill depend upon the means and purpose for which the compound of thepresent invention is being applied. Solvents are generally selectedbased on solvents recognized by persons skilled in the art as safe(GRAS) to be administered to a mammal. In general, safe solvents arenon-toxic aqueous solvents such as water and other non-toxic solventsthat are soluble or miscible in water. Suitable aqueous solvents includewater, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400,PEG 300), etc. and mixtures thereof. The formulations may also includeone or more buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents and other known additivesto provide an elegant presentation of the drug (i.e., a compound of thepresent invention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the Formula I compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable dosage of the drug and to enablepatient compliance with the prescribed regimen.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Pharmaceutical formulations of the compounds of the present inventionmay be prepared for various routes and types of administration. Forexample, a compound of Formula I having the desired degree of purity mayoptionally be mixed with pharmaceutically acceptable diluents, carriers,excipients or stabilizers (Remington's Pharmaceutical Sciences (1980)16th edition, Osol, A. Ed.), in the form of a lyophilized formulation,milled powder, or an aqueous solution. Formulation may be conducted bymixing at ambient temperature at the appropriate pH, and at the desireddegree of purity, with physiologically acceptable carriers, i.e.,carriers that are non-toxic to recipients at the dosages andconcentrations employed. The pH of the formulation depends mainly on theparticular use and the concentration of compound, but may range fromabout 3 to about 8. Formulation in an acetate buffer at pH 5 is asuitable embodiment.

The compound of this invention for use herein is preferably sterile. Inparticular, formulations to be used for in vivo administration must besterile. Such sterilization is readily accomplished by filtrationthrough sterile filtration membranes.

The compound ordinarily can be stored as a solid composition, alyophilized formulation or as an aqueous solution.

The pharmaceutical compositions of the invention comprising a Formula Icompound will be formulated, dosed and administered in a fashion, i.e.,amounts, concentrations, schedules, course, vehicles and route ofadministration, consistent with good medical practice. Factors forconsideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners. The“therapeutically effective amount” of the compound to be administeredwill be governed by such considerations, and is the minimum amountnecessary to prevent, ameliorate, or treat the coagulation factormediated disorder. Such amount is preferably below the amount that istoxic to the host or renders the host significantly more susceptible tobleeding.

As a general proposition, the initial pharmaceutically effective amountof the Formula I compound administered parenterally per dose will be inthe range of about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg ofpatient body weight per day, with the typical initial range of compoundused being 0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Theactive pharmaceutical ingredients may also be entrapped in microcapsulesprepared, e.g., by coacervation techniques or by interfacialpolymerization, e.g., hydroxymethylcellulose or gelatin-microcapsulesand poly-(methylmethacylate) microcapsules, respectively, in colloidaldrug delivery systems (e.g., liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington's Pharmaceutical Sciences16th edition, Osol, A. Ed. (1980).

Sustained-release preparations of Formula I compounds may be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (e.g.,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

Formulations of a compound of Formula I suitable for oral administrationmay be prepared as discrete units such as pills, capsules, cachets ortablets each containing a predetermined amount of a compound of FormulaI.

Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs may be prepared for oral use. Formulationsof compounds of Formula I intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipient which are suitable formanufacture of tablets are acceptable. These excipients may be, e.g.,inert diluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets may be uncoated or may be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations may be applied as a topical ointment or creamcontaining the active ingredient(s) in an amount of, e.g., 0.075 to 20%w/w. When formulated in an ointment, the active ingredients may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base.

If desired, the aqueous phase of the cream base may include a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol (including PEG 400) and mixtures thereof. Thetopical formulations may desirably include a compound which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethyl sulfoxide and related analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

Aqueous suspensions of Formula I compounds contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension may also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

The pharmaceutical compositions of compounds of Formula I may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butanediol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, about 0.5 to10% w/w, or about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising e.g. cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size e.g. in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers,e.g. sealed ampoules and vials, and may be stored in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, e.g. water, for injection immediately prior to use.Extemporaneous injection solutions and suspensions are prepared fromsterile powders, granules and tablets of the kind previously described.Preferred unit dosage formulations are those containing a daily dose orunit daily sub-dose, as herein above recited, or an appropriate fractionthereof, of the active ingredient.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

Combination Therapy

The compounds of Formula I may be employed alone or in combination withother therapeutic agents for the treatment of a disease or disorderdescribed herein, such as a hyperproliferative disorder (e.g., cancer).In certain embodiments, a compound of Formula I is combined in apharmaceutical combination formulation, or dosing regimen as combinationtherapy, with a second compound that has anti-hyperproliferativeproperties or that is useful for treating a hyperproliferative disorder(e.g., cancer). The second compound of the pharmaceutical combinationformulation or dosing regimen preferably has complementary activities tothe compound of Formula I such that they do not adversely affect eachother. Such compounds are suitably present in combination in amountsthat are effective for the purpose intended. In one embodiment, acomposition of this invention comprises a compound of Formula I, incombination with a chemotherapeutic agent such as described herein.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein preferably there is a time period while both (orall) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other chemotherapeutic agents ortreatments.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes,separate pills or capsules, or separate infusions. In general, duringalternation therapy, an effective dosage of each active ingredient isadministered sequentially, i.e., serially, whereas in combinationtherapy, effective dosages of two or more active ingredients areadministered together.

In a particular embodiment of anti-cancer therapy, a compound of FormulaI, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite,or pharmaceutically acceptable salt or prodrug thereof, may be combinedwith other chemotherapeutic, hormonal or antibody agents such as thosedescribed herein, as well as combined with surgical therapy andradiotherapy. Combination therapies according to the present inventionthus comprise the administration of at least one compound of Formula I,or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof, and the use of atleast one other cancer treatment method. The amounts of the compound(s)of Formula I and the other pharmaceutically active chemotherapeuticagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

Metabolites of Formula I Compounds

Also falling within the scope of this invention are the in vivometabolic products of Formula I described herein. Such products mayresult e.g. from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound. Accordingly, the inventionincludes metabolites of compounds of Formula I, including compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof.

Metabolite products typically are identified by preparing aradiolabelled (e.g., 14C or 3H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or

NMR analysis. In general, analysis of metabolites is done in the sameway as conventional drug metabolism studies well known to those skilledin the art. The metabolite products, so long as they are not otherwisefound in vivo, may be useful in diagnostic assays for therapeutic dosingof the compounds of the invention.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the diseases anddisorders described above is provided. The kit comprises a containercomprising a compound of Formula I. The kit may further comprise a labelor package insert, on or associated with the container. The term“package insert” is used to refer to instructions customarily includedin commercial packages of therapeutic products, that contain informationabout the indications, usage, dosage, administration, contraindicationsand/or warnings concerning the use of such therapeutic products.Suitable containers include, e.g., bottles, vials, syringes, blisterpack, etc. The container may be formed from a variety of materials suchas glass or plastic. The container may hold a compound of Formula I orII or a formulation thereof which is effective for treating thecondition and may have a sterile access port (e.g., the container may bean intravenous solution bag or a vial having a stopper pierceable by ahypodermic injection needle). At least one active agent in thecomposition is a compound of Formula I. The label or package insertindicates that the composition is used for treating the condition ofchoice, such as cancer. In addition, the label or package insert mayindicate that the patient to be treated is one having a disorder such asa hyperproliferative disorder, neurodegeneration, cardiac hypertrophy,pain, migraine or a neurotraumatic disease or event. In one embodiment,the label or package inserts indicates that the composition comprising acompound of Formula I can be used to treat a disorder resulting fromabnormal cell growth. The label or package insert may also indicate thatthe composition can be used to treat other disorders. Alternatively, oradditionally, the article of manufacture may further comprise a secondcontainer comprising a pharmaceutically acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of thecompound of Formula I and, if present, the second pharmaceuticalformulation. For example, if the kit comprises a first compositioncomprising a compound of Formula I, and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I or II, such as tablets orcapsules. Such a kit preferably includes a number of unit dosages. Suchkits can include a card having the dosages oriented in the order oftheir intended use. An example of such a kit is a “blister pack”.Blister packs are well known in the packaging industry and are widelyused for packaging pharmaceutical unit dosage forms. If desired, amemory aid can be provided, e.g. in the form of numbers, letters, orother markings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

According to one embodiment, a kit may comprise (a) a first containerwith a compound of Formula I contained therein; and optionally (b) asecond container with a second pharmaceutical formulation containedtherein, wherein the second pharmaceutical formulation comprises asecond compound with anti-hyperproliferative activity. Alternatively, oradditionally, the kit may further comprise a third container comprisinga pharmaceutically-acceptable buffer, such as bacteriostatic water forinjection (BWFI), phosphate-buffered saline, Ringer's solution anddextrose solution. It may further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, needles, and syringes.

In certain other embodiments wherein the kit comprises a composition ofFormula I and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

Preparation of Formula I Compounds

Benzoxazepin compounds of Formula I may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Aldrich Chemicals (Milwaukee, Wis.) or are readilyprepared using methods well known to those skilled in the art (e.g.,prepared by methods generally described in Louis F. Fieser and MaryFieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements (also available via theBeilstein online database).

In certain embodiments, compounds of Formula I may be readily preparedusing well-known procedures to prepare benzoxepin compounds (Sekhar etal (1989) Sulfur Letters 9(6):271-277; Katsura et al (2000 J. Med. Chem.43:3315-3321; Rueeger et al (2004) Biorganic & Med. Chem. Letters14:2451-2457; Reiter et al (2007) Biorganic & Med. Chem. Letters17:5447-5454; Banaszak et al (2006) Tetrahedron Letters 47:6235-6238;)and other heterocycles, which are described in: ComprehensiveHeterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997,e.g. Volume 3; Liebigs Annalen der Chemie, (9):1910-16, (1985);Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung,40(12):1328-31, (1990).

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, e.g. 5 to 1,000 compounds, or 10 to 100compounds. Libraries of compounds of Formula I may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesesusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art. Thus according to a further aspect ofthe invention there is provided a compound library comprising at least 2compounds, or pharmaceutically acceptable salts thereof.

For illustrative purposes, the General Procedures show general methodswhich may be applied for preparation of Formula I compounds, as well askey intermediates. The Figures and Examples sections contain moredetailed description of individual reaction steps. Those skilled in theart will appreciate that other synthetic routes may be used tosynthesize the inventive compounds. Although certain starting materialsand routes are depicted in the Schemes, General Procedures and Examples,other similar starting materials and routes can be substituted toprovide a variety of derivatives and/or reaction conditions. Inaddition, many of the compounds prepared by the methods described belowcan be further modified in light of this disclosure using conventionalchemistry well known to those skilled in the art.

In preparing compounds of Formulas I, protection of remote functionality(e.g., primary or secondary amine) of intermediates may be necessary.The need for such protection will vary depending on the nature of theremote functionality and the conditions of the preparation methods.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, Third Ed., 1999.

Methods of Separation

In the methods of preparing the compounds of this invention, it may beadvantageous to separate reaction products from one another and/or fromstarting materials. The desired products of each step or series of stepsis separated and/or purified (hereinafter separated) to the desireddegree of homogeneity by the techniques common in the art. Typicallysuch separations involve multiphase extraction, crystallization from asolvent or solvent mixture, distillation, sublimation, orchromatography. Chromatography can involve any number of methodsincluding, e.g.: reverse-phase and normal phase; size exclusion; ionexchange; high, medium and low pressure liquid chromatography methodsand apparatus; small scale analytical; simulated moving bed (SMB) andpreparative thin or thick layer chromatography, as well as techniques ofsmall scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.(1982) 47:4165), of the racemic mixture, and analyzing the 1H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

General Preparative Procedures

FIGS. 1-20 show general methods for preparation of Formula Ibenzoxazepin compounds and intermediates.

FIG. 1 shows a general exemplary route to benzoxepin compounds 3

FIG. 2 shows a synthetic route to9-halo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinecompounds 12 from 4-bromo-2-hydroxybenzaldehyde 4.

FIG. 3 shows a synthetic route to7-bromo-5-chloro-2,3-dihydrobenzo[f][1,4]oxazepine 16 and7-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-imine 19

FIG. 4 shows synthetic routes to(E)-8-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine 23

FIG. 5 shows synthetic routes to10-bromo-2-phenyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 27 and10-bromo-2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine30

FIG. 6 shows a synthetic route to9-halo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinecompounds 12 from 4-bromo-2-fluorobenzonitrile 20.

FIG. 7 shows a synthetic route to9-halo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinecompounds 12 from the reaction of(E)-8-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine 23 and2-chloro-1-(1-isopropyl-1H-1,2,4-triazol-5-yl)ethanone 36.

FIG. 8 shows a synthetic route to8-chloro-3,4-dihydrooxepino[3,2-c]pyridin-5(2H)-one 42

FIG. 9 shows a synthetic route to2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol176

FIG. 10 shows conversion of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride 47 to 191, 192, 197, 198, 200.

FIG. 11 shows a synthetic route to2-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)-2-methylpropanamide205 and3-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)oxetane-3-carboxamide56 from8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride 47

FIG. 12 shows a synthetic route to8-Azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene59

FIG. 13 shows a synthetic route to2-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)azetidin-1-yl)ethanol169 and2-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)azetidin-1-yl)-2-methylpropan-1-ol170 from9-(azetidin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine144.

FIG. 14 shows a synthetic route to2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene68

FIG. 15 shows conversion of 68 to 175, 177, 178, 179, 189.

FIG. 16 shows a synthetic route to[4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-methanol188

FIG. 17 shows a synthetic route to9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine239

FIG. 18 shows a synthetic route to2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazepine88 (280)

FIG. 19 shows a synthetic route to tert-butyl5-(9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-ylcarbamatefrom 4-fluoro-2-hydroxybenzaldehyde

FIG. 20 shows a synthetic route to10-fluoro-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine281 from 5-fluoro-2-hydroxybenzaldehyde

EXAMPLES

The chemical reactions described in the Examples may be readily adaptedto prepare a number of other PI3K inhibitors of the invention, andalternative methods for preparing the compounds of this invention aredeemed to be within the scope of this invention. For example, thesynthesis of non-exemplified compounds according to the invention may besuccessfully performed by modifications apparent to those skilled in theart, e.g., by appropriately protecting interfering groups, by utilizingother suitable reagents known in the art other than those described,and/or by making routine modifications of reaction conditions.Alternatively, other reactions disclosed herein or known in the art willbe recognized as having applicability for preparing other compounds ofthe invention.

In the Examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Sigma Aldrich Chemical Company, andwere used without further purification unless otherwise indicated. Thereactions set forth below were conducted generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried. Columnchromatography was conducted on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SEP PAK®cartridge (Waters). 1H NMR spectra were obtained at 400 MHz indeuterated CDCl3, d6-DMSO, CH3OD or d6-acetone solutions (reported inppm), using chloroform as the reference standard (7.25 ppm). When peakmultiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd(doublet of doublets), dt (doublet of triplets). Coupling constants,when given, are reported in Hertz (Hz).

Liquid Chromatography Mass Spectrometry (LCMS) experiments to determineretention times (RT) and associated mass ions were performed usingvarious methods familiar to those skilled in the art of analyticalmethods of organic compounds.

Chemical structures were named according to: vendor designation; IUPACconvention; ChemDraw Ultra, Version 9.0.1, CambridgeSoft Corp.,Cambridge Mass.; or Autonom 2000 Name, MDL Inc. It is recognized bythose skilled in the art that a compound may have more than one name,according to different conventions.

Example 1 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

Step 1: ethyl 4-(3-bromophenoxy)butanoate

Solid 3-bromophenol (10.0 g, 58 mmol) was added portion wise to astirred suspension of K2CO3 in acetone (100 mL) at room temperature. seeFIG. 1. Sodium iodide (NaI, 1.0 g) was added, followed byethyl-4-bromobutyrate (9.2 mL, 64 mmol). The reaction mixture was heatedat 80° C. overnight, cooled to room temperature, diluted with water andextracted with ethylacetate to give ethyl 4-(3-bromophenoxy)butanoate.

Step 2: 4-(3-bromophenoxy)butanoic acid

Ethyl 4-(3-bromophenoxy)butanoate 6 from Example 5 was taken up in 100mL THF and 50 mL water and treated with lithium hydroxide LiOH (hydrate,4.9 g). see FIG. 1. The whole was heated at 50° C. for 2 days. Themixture was cooled to room temperature and acidified to pH 1 with 2NHCl. The aqueous was extracted with ethylacetate. The combined organicswere washed with brine and dried over sodium sulfate to give crude4-(3-Bromophenoxy)butanoic acid as a sticky solid. 1H NMR (DMSO-d6, 500MHz) 7.24 (m, 1H), 7.13 (m, 1H), 7.11 (m, 1H), 6.95 (m, 1H), 3.99 (m,2H), 2.37 (m, 2H), 1.94 (m, 2H).

Step 3: 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

To a stirred suspension of polyphosphoric acid (PPA, ca. 60 g) andcelite (ca. 40 g) in 100 mL toluene was added crude4-(3-bromophenoxy)butanoic acid 7 (ca. 58 mmol) in one portion, 10 mLtoluene rinse (FIG. 1). The resultant suspension was heated at 110° C.for 5 hr. The toluene was decanted through a plug of celite and theremaining slurry was washed repeatedly with toluene and ethylacetate.The eluent was concentrated and purified by flash column chromatography(4:1 hex:EtOAc) to give 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (7g, ca. 50% y). 1H NMR (DMSO-d6, 500 MHz) 7.55 (d, J=8.5 Hz, 1H), 7.37(d, J=1.5 Hz, 1H), 7.35 (dd, J=8.5, 1.5 Hz, 1H), 4.24 (t, J=6.5 Hz, 2H),2.79 (t, J=7.0 Hz, 2H), 2.14 (m, 2H).

Example 2 (Z)-8-bromo-5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde

Phosphorus oxychloride, POCl3 (1.88 mL, 20.8 mmol) was added dropwise toDMF (5 mL) at 0° C. After 30 min a solution of8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one 8 (2.0 g, 8.3 mmol) in 8 mLDMF was added dropwise. The reaction mixture was allowed to reach roomtemperature to stir 2 hr, then poured slowly over rapidly stirred icewater. The aqueous phase was extracted with ethylacetate and thecombined organics were washed with brine, dried over sodium sulfate andconcentrated to give(Z)-8-bromo-5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde.

Example 3 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

To a slurry of NaH (60% dispersion in mineral oil) (1.48 g, 37.1 mmol)in THF (˜50 mL) at room temperature was added1-(5-bromo-2-(2-bromoethoxy)phenyl)ethanone (8.07 g, 25.1 mmol). Thereaction mixture was slowly heated to reflux and allowed to stir for 20h. The solvent was removed under vacuum pressure and the concentratedresidue was absorbed onto silica gel and purified by columnchromatography (4:1 ethyl acetate/petroleum ether). The product wasafforded as a yellow oil after the solvents were removed, providing 4.22g (70%) of 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one. 1H NMR (CDCl3)7.87 (d, J=2.6 Hz, 1H), 7.50 (dd, J=2.6, 8.1 Hz, 1H), 6.97 (d, J=8.8 Hz,2H), 4.24 (t, J=6.6 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H), 2.15-2.29 (m, 2H).

Example 4 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

To 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3 g, 12 mmol) in ether(110 mL) was added bromine (0.7 mL, 14 mmol) and allowed to stir at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure and purified via ISCO chromatography (hexane to 20%hexane in EtOAc over 45 minutes). Collected fractions and concentratedto give 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3.53 g, 89%).1H NMR (500 MHz, CDCl3) δ 7.86 (d, J=2.5, 1H), 7.52 (dt, J=28.5, 14.2,1H), 6.97 (d, J=8.7, 1H), 4.95 (dd, J=7.6, 6.8, 1H), 4.53-4.36 (m, 1H),4.17 (ddd, J=12.8, 9.9, 4.4, 1H), 3.04-2.84 (m, 1H), 2.52 (ddt, J=14.7,7.8, 4.5, 1H)

Example 5 3-isopropyl-1-methyl-1H-1,2,4-triazol-5(4H)-one Step 1:1-methylhydrazinecarboxamide

Methylhydrazine and trimethylsilylisocyanate were reacted intetrahydrofuran at 0 C and then quenched and hydrolyzed with methanol togive 1-methylhydrazinecarboxamide.

Step 2: 2-isobutyryl-1-methylhydrazinecarboxamide

1-Methylhydrazinecarboxamide was acylated with isobutyryl chloride intriethylamine and dichloromethane to give2-isobutyryl-1-methylhydrazinecarboxamide.

Step 3: 3-isopropyl-1-methyl-1H-1,2,4-triazol-5(4H)-one

2-Isobutyryl-1-methylhydrazinecarboxamide was cyclized with10-camphorsulfonic acid at reflux in ethylacetate to give3-isopropyl-1-methyl-1H-1,2,4-triazol-5(4H)-one.

Example 6 1,3-dimethyl-1H-1,2,4-triazol-5(4H)-one and1-isopropyl-3-methyl-1H-1,2,4-triazol-5(4H)-one

Acetamide and ethyl chloroformate were mixed at 45 C to give thehydrochloride salt of ethyl acetimidate which was further reacted withethyl chloroformate, diisopropylethylamine, and dichloromethane at 0 Cto give ethyl N-ethoxycarbonylacetimidate which was reacted with methylhydrazine or isopropyl hydrazine hydrochloride in triethylamine andtoluene to give 1,3-dimethyl-1H-1,2,4-triazol-5(4H)-one and1-isopropyl-3-methyl-1H-1,2,4-triazol-5(4H)-one, respectively.

Example 7 4-isopropyl-1-(4-methoxybenzyl)-1H-imidazol-2(3H)-one

3-Methylbutan-2-one was brominated with bromine in methanol to give1-bromo-3-methylbutan-2-one which was reacted with 4-methoxybenzylamineand cyclized with sodium cyanate to give4-isopropyl-1-(4-methoxybenzyl)-1H-imidazol-2(3H)-one.

Example 8 Methyl6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate

Step 1: 2-Methyl-1-trityl-1H-imidazole

Triphenylmethyl chloride (16.0 g, 57.5 mmol) was added portionwise to asolution of 2-methylimidazole (4.10 g, 50.0 mmol) and Triethylamine(9.02 mL, 64.7 mmol) in20 ml of N,N-dimethylformamide. The mixture wasstirred for 18 hours, mixed with 300 ml of water and extracted with 1000ml of ethyl acetate. The organic extract was washed with 1 L of water,brine, dried over MgSO4 and concentrate in vacuum to 50 ml volume. Aprecipitate was collected, washed with ethyl acetate and dried in highvacuum for 18 hours. Weight 15.0 g (92.5%). 1H NMR (400 MHz, CDCl3) δ7.34-7.29 (m, 9H), 7.16-7.11 (m, 6H), 6.90 (d, J=1.5, 1H), 6.71 (d,J=1.5, 1H), 1.65 (s, 3H).

Step 2: 2-(1-trityl-1H-imidazol-2-yl)acetaldehyde

1.6 M of n-Butyllithium in hexane (7.5 mL) was added dropwise to asolution of 2-Methyl-1-trityl-1H-imidazole (3.244 g, 10.00 mmol) inTetrahydrofuran (100.0 mL, 1233 mmol) at at −76° C. The dark red mixturewas stirred for 45 min. Ethyl formate (4.039 mL, 50.00 mmol) was addedquickly and the mixture (turned yellowish) was stirred for 20 min. 6 mlof 5% aq. citric acid were added and the mixture was mixed with 60 ml ofaq citric acid and extracted with ethyl acetate. The organic layer waswashed with water, brine, dried over MgSO4 and concentrated in vacuum.Pale yellow semisolid material (2.025 g, 57.5%) was used in the nextstep without further purification.

Step 3: 2-(1-trityl-1H-imidazol-2-yl)ethanol

Crude 2-(1-trityl-1H-imidazol-2-yl)acetaldehyde (2.025 g (5.75 mmol) wasdissolved in MeOH/THF (1:1, 40 ml) and NaBH4 (0.435 g, 11.5 mmol) wasadded portionwise to the above mixture. The mixture was stirred for 18hours, diluted with 100 ml of water and extracted with 2× DCM. Thecombined organic extracts were washed with water, brine, dried overNa2SO4 and concentrated in vacuum. Weight of the residue 1.915 g (94%).1H NMR (500 MHz, CDCl3) δ 7.35-7.31 (m, 9H), 7.12 (dd, J=6.7, 2.7, 6H),6.93 (d, J=1.0, 1H), 6.74 (d, J=1.0, 1H), 5.04 (br, 1H), 3.46 (t, J=5.4,2H), 2.00 (t, J=5.4, 2H).

Step 4: Methyl 6-iodo-5-(2-(1-trityl-1H-imidazol-2-yl)ethoxy)nicotinate

Diisopropyl azodicarboxylate (1160 uL, 5.90 mmol) was added dropwise toa mixture of 2-(1-trityl-1H-imidazol-2-yl)ethanol (1900 mg, 5.4 mmol),methyl 5-hydroxy-6-iodonicotinate (1570 mg, 5.63 mmol) andTriphenylphosphine (1550 mg, 5.90 mmol) in Tetrahydrofuran (45.0 mL, 555mmol) at 0° C. After stirring for 3 hours the mixture was mixed withwater and extracted with ethyl acetate. The organic layer was washedwith water, brine, dried over MgSO4 and concentrated in vacuum. Theresidue was purified on 40 g silica column eluting with 50% ethylacetate in DCM to give 1.45 g (44%) of methyl6-iodo-5-(2-(1-trityl-1H-imidazol-2-yl)ethoxy)nicotinate. MS(ESI+):616.0. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=1.9, 1H), 7.40-7.28 (m,10H), 7.20-7.16 (m, 6H), 6.99 (d, J=1.5, 1H), 6.81 (d, J=1.5, 1H),3.98-3.91 (m, 5H), 2.46 (t, J=7.3, 2H).

Step 5: Methyl 5-(2-(1H-imidazol-2-yl)ethoxy)-6-iodonicotinate

Triethylsilane (0.160 mL, 1.00 mmol) was added to a solution of 1.45 g(2.36 mmol) of methyl6-iodo-5-(2-(1-trityl-1H-imidazol-2-yl)ethoxy)nicotinate intrifluoroacetic acid (30.0 mL, 389 mmol). The mixture was stirred for 4hours, concentrated in vacuum and triturated with 50 ml of anhydrousethyl ether. The solid material was collected, washed with severalportions of ether and partitioned between 1 M of aqueous sodiumcarbonate and ethyl acetate. The organic extracts were washed withwater, brine, dried over magnesium sulfate and concentrated in vacuum togive a residue (0.55 g, 62%) of methyl5-(2-(1H-imidazol-2-yl)ethoxy)-6-iodonicotinate. MS(ESI+): 374.0

Step 6: Methyl6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate

A mixture of methyl 5-(2-(1H-imidazol-2-yl)ethoxy)-6-iodonicotinate (373mg, 1.00 mmol), Copper(I) oxide (14.3 mg, 0.10 mmol), Ninhydrin (35.6mg, 0.20 mmol) and potassium carbonate (290 mg, 2.10 mmol) in dimethylsulfoxide (10.0 mL) was heated at 110° C. for 2 hours. The mixture waspoured into 20 ml of water and extracted with ethyl acetate (3×15 ml).The organic extracts were washed with water (3×15 ml), brine, dried overMgSO4 and concentrated. The residue (0.220 g, 90%) was used withoutfurther purification in the next step. MS(ESI+): 246.0. 1H NMR (500 MHz,CDCl3) δ 8.77 (d, J=1.9, 1H), 8.10 (s, 1H), 8.04 (d, J=1.9, 1H), 7.08(s, 1H), 4.47 (t, J=5.1, 2H), 3.97 (s, 3H), 3.46 (t, J=5.1, 2H).

Example 9 Methyl9,10-diiodo-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate

N-Iodosuccinimide (394 mg, 1.75 mmol) was added to a solution of methyl5-(2-(1H-imidazol-2-yl)ethoxy)-6-iodonicotinate (220 mg, 0.90 mmol) inN,N-Dimethylformamide (8.0 mL, 1.0E2 mmol). The mixture was stirred for6 hours at room temperature and 18 hours at 60° C. The mixture wasconcentrated in vacuum and the residue was partitioned between ethylacetate and 1M aq Na2CO3. The organic layer was washed with water,brine, dried over Na2SO4 and concentrated. The residue was purified on a4 g silica column eluting with 40% of ethyl acetate in heptane. Weight130 mg. MS(ESI+): 497.9. 1H NMR (500 MHz, CDCl3) δ 9.02 (d, J=1.9, 1H),8.21 (d, J=1.9, 1H), 4.65 (t, J=6.4, 2H), 4.00 (s, 3H), 3.14 (t, J=6.4,2H).

Example 10 Methyl10-iodo-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate

Ethylmagnesium bromide in ethyl ether (3.0 M, 0.104 mL, 0.31 mmol)) wasadded dropwise to a suspension of methyl9,10-diiodo-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate(130 mg, 0.26 mmol) in Tetrahydrofuran (5.0 mL, 62 mmol) at at −15° C.The mixture was stirred for 15-20 min (a completion was monitored byLCMS), pour into 20 ml of sat. aq. NH4Cl and extracted with ethylacetate. The organic extracts were washed with water (2×20 ml), brine,dried over MgSO4 and concentrated in vacuum. Weight 92 mg (94%).MS(ESI+): 372.0.

Example 11 Methyl9-(1-isopropyl-1H-pyrazol-5-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate

A mixture of1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(117.1 mg, 0.4958 mmol), methyl10-iodo-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate(92.0 mg, 0.248 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (20.24 mg, 0.02479 mmol) and 1.0 M ofPotassium acetate in water (0.49 mL) in 1,2-Dimethoxyethane (5.0 mL, 48mmol) was degassed. The reaction was microwaved on 200 watts, 140° C.for 40 minutes. The reaction mixture was filtered, washed with DME,mixed with water and extracted with EtOAc. Combined organic extractswere washed with 1% aq NaOH to remove a phenolic byproduct, then 5% aqcitric acid, water, brine, dried over Na2SO4 and concentrated in vacuum.The residue was purified on 4 g silica column, eluting with 60-70% ofEtOAc in heptane. Yield 21 mg. MS(ESI+): 354.2.

Example 129-(1-Isopropyl-1H-pyrazol-5-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylicacid

A mixture of 21 mg (0.06 mmol) of methyl9-(1-isopropyl-1H-pyrazol-5-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylateand 1.0 ml of 1 N aq LiOH in 4 ml of methanol and 4 ml oftetrahydrofuran was stirred for 6 hours. The mixture was acidified to pH3 by addition of 1 N HCl and concentrated in vacuum. The residue waspartitioned between ethyl acetate and water, the organic layer waswashed with brine, dried over Na2SO4 and concentrated. Yield 17 mg.MS(ESI+): 340.1

Example 13 Methyl2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate

A mixture of methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate(370.1 mg, 1.000 mmol),1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(354 mg, 1.50 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (40.8 mg, 0.0500 mmol) and 2.0 M of Potassiumacetate in water (1.00 mL) in Acetonitrile (12 mL, 230 mmol) wasdegassed. The reaction was microwaved on 200 watts, 140° C. for 30minutes. The reaction mixture was partitioned between water and ethylacetate, filtered, the organic layer was washed with water, brine, driedover MgSO4 and concentrated in vacuum. The residue was purified on 12 gsilica column eluting with 35-40% ethyl acetate in heptane. Yield 119 mg(34%). MS: (ESI+): 353.1.

Example 142-(1-Isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid

Following the procedure in Example 10, methyl2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylatewas hydrolized to give2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid. MS(ESI+): 339.4.

Example 15 Methyl2-(4-cyano-1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate

Step 1: 5-Amino-1-isopropyl-1H-pyrazole-4-carbonitrile

Sodium methoxide (2.139 g, 39.60 mmol) was added to a solution ofethoxymethylenemalonitrile (2.198 g, 18.00 mmol) and isopropylhydrazinehydrochloride (2.212 g, 20.00 mmol) in Ethanol (50 mL, 800 mmol). Themixture was heated under reflux for 18 hours. The solvent was removed invacuum, the residue partitioned between ethyl acetate and water. Theorganic layer was washed with water, brine, dried over Na2SO4,concentrated in vacuum and purified on 25 g silica column, eluting with25-30% of ethyl acetate in heptane, to give5-Amino-1-isopropyl-1H-pyrazole-4-carbonitrile (yield 1.77 g, 65%).MS(ESI+): 151.2. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=6.4, 1H), 4.23(ddd, J=19.8, 16.6, 9.8, 3H), 1.46 (d, J=6.6, 7H).

Step 2: 5-Iodo-1-isopropyl-1H-pyrazole-4-carbonitrile

Amyl nitrite (13.00 g, 111.0 mmol) was added to a suspension of5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (1.77 g, 11.8 mmol) inDiiodomethane (56.0 mL, 695 mmol) at −10° C. in 30 min. The mixture wasstirred for 30 min at room temperature and then heated at 100° C. for 2hours. The mixture was then cooled and concentrated in high vacuum togive a residue which was partitioned between ethyl acetate and 5%Na2SO5. The organic layer was washed with water, 0.1% of aq HCl, water,brine, dried and concentrated in vacuum. The residue was purified onsilica column eluting with 20-30% ethyl acetate in heptane. Yield 1.68 g(55%). MS(ESI+): 262.2

Step 3: Methyl2-(tributylstannyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate

Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 1.5 mL, 3.00mmol) was added dropwise to a solution of methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate(740 mg, 2.00 mmol) in Tetrahydrofuran (12 mL, 150 mmol) at roomtemperature. The mixture was stirred for 2.5 hours. Tributyltin chloride(0.8138 mL, 3.000 mmol) was added and the mixture was stirred for 18hours. The mixture was mixed with sat aq. NH4Cl and extracted with ethylacetate. The organic layer was washed with brine, dried over Na2SO4 andpurified on 25 g silica column eluting with 15-20% ethyl acetate inheptane. Yield 160 mg (15%). MS(ESI+): 535.2

Step 4: Methyl2-(4-cyano-1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate

A mixture of methyl2-(tributylstannyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate(155 mg, 0.291 mmol), 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile(133 mg, 0.509 mmol) and Tetrakis(triphenylphosphine)palladium(0) (16.8mg, 0.0145 mmol) in Toluene (6.0 mL, 56 mmol) was heated for 18 hours.The mixture was concentrated in vacuum, the residue purified on 4 gsilica column eluting with 30% ethyl acetate in heptane. Yield 65 mg(59%). MS(ESI+): 378.2

Example 162-(4-cyano-1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid

Following the procedure in Example 10, methyl2-(4-cyano-1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylatewas hydrolyzed to give2-(4-cyano-1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid. MS(ESI+): 364.3

Example 1710-Chloro-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine Step 1:2-Chloro-5-(methoxymethoxy)pyridine

Sodium hydride, 60% dispension in mineral oil (3:2, Sodiumhydride:Mineral Oil, 2.32 g) was added portion wise to a solution of6-Chloro-pyridin-3-ol (5.00 g, 38.6 mmol) in a mixture ofTetrahydrofuran (10.0 mL, 123 mmol) and N,N-Dimethylformamide (20.0 mL,258 mmol). The mixture formed was stirred for 15 min and ChloromethylMethyl Ether (3.66 mL, 48.2 mmol) was added dropwise. The above mixturewas stirred for 6 hours (monitored by LCMS), poured into water andextracted with ethyl acetate. The organic extracts were washed withwater, brine, dried over MgSO4 and concentrated in vacuum. Purified on40 g silica column eluting with 10-40% ethyl acetate in heptane to give6.33 g of 2-chloro-5-(methoxymethoxy)pyridine.

Step 2: 2-Chloro-5-(methoxymethoxy)isonicotinaldehyde

tert-Butyllithium in pentane (1.7 M, 19.0 mL) was added dropwise to asolution of 2-chloro-5-(methoxymethoxy)pyridine (4.880 g, 28.11 mmol) in100 ml of ethyl ether at −76° C. Some precipitate appeared. The mixturewas kept at −76° C. for 20 min then N,N-dimethylformamide (2.938 mL,37.95 mmol) was added dropwise. The mixture was stirred for 10 min at−76° C. and then allowed to warm to at 0° C. for 1 h period. 10% aqNH4Cl was added and the mixture was extracted with ethyl acetate. Theorganic solution was washed with water, brine and dried over Na2SO4.After concentration in vacuum the yield of the crude2-chloro-5-(methoxymethoxy)isonicotinaldehyde 5.49 g. MS: 202.0, 172.0.Without further purification was used in the next step.

Step 3: 2-chloro-4-(1H-imidazol-2-yl)-5-(methoxymethoxy)pyridine

Crude 2-chloro-5-(methoxymethoxy)isonicotinaldehyde (5.20 g, 25.87 mmol)was dissolved in 60 ml of methanol and mixed with 40% aqueous ethanedial(16.31 g, 112.4 mmol) and aqueous ammonia (19.15 g, 337.3 mmol). Themixture was stirred for 3 hours, concentrated in vacuum and acidified topH<1 with 60 ml of 1 N aq HCl. The aqueous solution was extracted withethyl acetate (3×30 ml). The organic extracts were discarded whileaqueous was basified by addition of sat NaHCO3. The mixture wasextracted with ethyl acetate (3×30 ml), combined organic extracts werewashed with water, brine, dried and concentrated in vacuum. The residue(crude 4.185 g) was purified on 40 g silica column eluting with 60-70%of ethyl acetate in heptane to yield 2.06 g of2-chloro-4-(1H-imidazol-2-yl)-5-(methoxymethoxy)pyridine (33%).MS(ESI+): 208 (loss of HOMe). 1H NMR (500 MHz, CDCl3) δ 10.56 (s, 1H),8.35 (s, 1H), 8.23 (s, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 5.43 (s, 2H),3.54 (d, J=14.0, 3H).

Step 4: 6-Chloro-4-(1H-imidazol-2-yl)pyridin-3-ol

Hydrogen chloride in dioxane (4 M, 40 mL) was added dropwise to asolution of 2.06 g (8.60 mmol) of2-chloro-4-(1H-imidazol-2-yl)-5-(methoxymethoxy)pyridine in Methylenechloride (40 mL, 600 mmol). The suspension was stirred for 2 hours andfiltered. The solid was washed with DCM, ether and dried in vacuum.Yield of 6-chloro-4-(1H-imidazol-2-yl)pyridin-3-ol dihydrochloride 2.31g (100%). MS(ESI+): 196.2. 1H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 8.14(s, 1H), 7.96 (s, 1H), 7.42 (s, 2H).

Step 5: 10-Chloro-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine

A mixture of 2.30 g (8.55 mmol) of6-chloro-4-(1H-imidazol-2-yl)pyridin-3-ol dihydrochloride,1,2-dibromoethane (1.842 mL, 21.37 mmol) and Cesium Carbonate (19.46 g,59.74 mmol) in 120 ml of N,N-Dimethylformamide was heated for 3 hours at90° C. The mixture was filtered and concentrated in high vacuum to give10-Chloro-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine. Weight1.88 g (99%) MS(ESI+): 222.2. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H),8.17 (s, 1H), 7.24 (d, J=1.0, 1H), 7.10 (d, J=0.9, 1H), 4.51-4.45 (m,4H).

Example 1810-chloro-2,3-diiodo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine

N-Iodosuccinimide (5.771 g, 25.65 mmol) was added to 1.89 g (8.55 mmol)of 10-chloro-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine inN,N-dimethylformamide (28 mL, 360 mmol) and the mixture was heated at80° C. for 48 hours. A precipitate was collected, washed with DMF andethyl ether and dried on air and then in high vacuum. Weight 2.85 g(70%). MS:473.9. 1H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 8.19 (s, 1H),4.53-4.46 (m, 2H), 4.45-4.38 (m, 2H).

Example 1910-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine

Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 3.311 mL) wasadded dropwise to a solution of10-chloro-2,3-diiodo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine(2.850 g, 6.020 mmol) in 110 ml of tetrahydrofuran at −10° C. Themixture was allowed to warm to 10° C. in 45 min and then mixed with 250ml of cold 10% NH4Cl. The organic layer was washed with brine and driedover Na2SO4. Concentration in vacuum afforded 2.06 g of10-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine(98.5%). MS: 348.0. 1H NMR (500 MHz, CDCl3) δ 8.33 (d, J=10.1, 1H), 8.18(s, 1H), 7.18 (s, 1H), 4.46 (q, J=5.8, 4H).

Example 2010-Chloro-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-2-carboxamide

A mixture of10-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine(2056 mg, 5.916 mmol), bis(triphenylphosphine)palladium(II) chloride(2.10E2 mg, 0.300 mmol) and hexamethyldisilazane (7.488 mL, 35.50 mmol)in 60 ml of N,N-Dimethylformamide was subjected to carbonylation at 1atm with CO from balloon. The reaction mixture was heated at 70° C. for1 h. The mixture was concentrated in vacuum, the residue partitionedbetween ethyl acetate and 1 M aqueous sodium carbonate. The organicextracts were washed with water, brine, dried over magnesium sulfate,concentrated in vacuum and purified on a 12 g silica column eluting with0-5% MeOH in DCM to give 1300 mg (83%). MS(ESI+): 265.0. 1H NMR (500MHz, DMSO) δ 8.37 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.70 (s, 1H),7.25 (s, 1H), 4.56 (s, 4H).

Example 2110-Chloro-N-((dimethylamino)methylene)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-2-carboxamide

A mixture of10-chloro-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-2-carboxamide(1.290 g, 4.875 mmol) and 1,1-Dimethoxy-N,N-dimethylmethanamine (3.238mL, 24.37 mmol) in 70 ml of toluene was heated under reflux for 1 hour.After cooling the product precipitated from the reaction mixture,collected, washed with ethyl ether and dried on air. Weight 0.705 g(85%). MS(ESI+): 320.1

Example 2210-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine

A mixture of 660 mg (2.06 mmol) of10-chloro-N-((dimethylamino)methylene)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-2-carboxamideand isopropylhydrazine hydrochloride (0.332 g, 3.00 mmol) in 44 ml ofacetic acid was heated at 85° C. for 3 hours. The mixture was cooled,filtered and mixed with 15 ml of water. A precipitate was filtered out,washed with water and dried in high vacuum. The above solid wastriturated with 1o ml of ethyl acetate, filtered out, washed with ethylacetate, ethyl ether and dried on air. Yield 0.710 g. MS: 331.2. 1H NMR(500 MHz, DMSO) δ 8.26 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.96 (s,1H), 5.76 (dt, J=13.1, 6.6, 1H), 4.62 (q, J=5.6, 4H), 1.50 (d, J=6.6,6H).

Example 23 methyl 4-hydroxy-3-(1H-imidazol-2-yl)benzoate

Following the procedure in Example 22, methyl 3-formyl-4-hydroxybenzoatewas coupled with ethanal and ammonia to give methyl4-hydroxy-3-(1H-imidazol-2-yl)benzoate. Yield 78%. MS(ESI+): 219.1

Example 24 methyl5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate

Following the procedure in Example 17, methyl4-hydroxy-3-(1H-imidazol-2-yl)benzoate reacted with 1,2-dibromoethane togive methyl5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. Yield76%. MS(ESI+): 245.0. 1H NMR (400 MHz, CDCl3) δ 9.21 (d, J=2.2, 1H),7.91 (dd, J=8.6, 2.2, 1H), 7.20 (t, J=4.8, 1H), 7.05 (d, J=8.6, 1H),7.00 (d, J=0.8, 1H), 4.53-4.48 (m, 2H), 4.43-4.39 (m, 2H), 3.91 (d,J=5.9, 3H).

Example 25 methyl2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate

A mixture of methyl5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate (2670 mg,9.29 mmol) and N-Iodosuccinimide (5230 mg, 23.2 mmol) in 100 ml ofN,N-Dimethylformamide was heated at 80° C. for 3 hours. The mixture wasmixed 300 ml of water and extracted 3×120 ml of methylene chloride. Thecombined organic extracts were washed with 5% aq sodium bicarbonate,2×50 ml of 10% aq sodium thiosulfate, water, brine, dried over MgSO4 andconcentrated in vacuum to a small volume. The precipitate was filtered,washed with methylene chloride and dried in vacuum. Yield 3.86 g (84%).MS 497.0. 1H NMR (500 MHz, CDCl3) δ 9.12 (d, J=2.0, 1H), 7.93 (dd,J=8.6, 2.1, 1H), 7.05 (d, J=8.6, 1H), 4.55-4.46 (m, 2H), 4.38 (dd,J=5.0, 2.9, 2H), 3.92 (s, 3H).

Example 26 methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate

Following the procedure in Example 26, methyl2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylatewas converted to methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate.Yield 95%. MS(ESI+): 370.9. 1H NMR (400 MHz, CDCl3) δ 9.15 (d, J=2.1,1H), 7.92 (dd, J=8.6, 2.2, 1H), 7.08 (s, 1H), 7.04 (t, J=7.9, 1H), 4.48(dd, J=9.5, 5.5, 2H), 4.40 (dd, J=9.4, 5.5, 2H), 3.92 (s, 3H).

Example 27 methyl2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate

2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate(370.1 mg, 1.0 mmol) and Copper cyanide (268.6 mg, 3.000 mmol) weremixed in 8 ml of N,N-Dimethylformamide. The reaction was microwaved on200 watts, 150° C., for 40 minutes. The reaction mixture was partitionedbetween 25 ml of 5% ammonia in water and 25 ml of EtOAc. The aqueouslayer was additionally extracted with 3×20 ml EtOAc, combined extractswere washed with water, brine and dried over MgSO4 to afford 225 mg ofmethyl2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate.Yield 81%. (MS: 270.0).

Example 28 methyl2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate

Methyl2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate(220 mg, 0.82 mmol) was dissolved in 4.0 ml of dimethyl sulfoxide andtreated with a solution of potassium carbonate (136 mg, 0.980 mmol) inwater (1.60 mL, 88.8 mmol). After cooling at 0° C., hydrogen peroxide(0.751 mL, 9.80 mmol) was added slowly. The mixture was stirred at roomtemperature for 2 hours. The mixture was diluted with20 ml of water andextracted with ethyl acetate (3×20 ml). The oprganic extracts werewashed with 5% sodium thiosufate, sat. NaHCO3, brine, dried over sodiumsulfate and concentrated to give 180 mg (77%) of crude methyl2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate.MS(ESI+): 288.0.

Example 29 methyl2-((dimethylamino)methylenecarbamoyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate

Following the procedure in Example 21, methyl2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylatewas converted to methyl2-((dimethylamino)methylenecarbamoyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylateYield 82%. MS(ESI+): 343.1

Example 30 methyl2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate

Following the procedure in Example 22, methyl2-((dimethylamino)methylenecarbamoyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylatewas coupled with 2-chlorophenylhydrazine hydrochloride to give methyl2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate.Yield 59%. MS(ESI+): 422.1

Example 312-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid

Following the procedure in Example 12, methyl2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylatewas hydrolyzed to give2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid. Yield 75%. MS(ESI+): 408.1

Example 339-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbaldehyde

Ethylmagnesium bromide in ethyl ether (3.0 M, 3.472 mL) was addeddropwise to a solution of9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1173 mg,3.000 mmol) in 20 ml of tetrahydrofuran at −30° C. The mixture wasstirred at this temperature for 20 min and allowed to warm to 15° C. Themixture was cooled to −25° C. again and N,N-dimethylformamide (929.2 uL,12.00 mmol) was added. The mixture was left for 18 hours. The mixturewas quenched with sat. aq. NH4Cl and extracted with ethyl acetate. Theorganic extracts were washed with water, brine, dried over mgSO4 andconcentrated in vacuum. Yield 0.92 g. MS: 293.1

Example 349-bromo-2-(4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Ammonia in water (16.0 M, 0.819 mL) was added to a solution of9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbaldehyde(640 mg, 2.2 mmol) and pyruvaldehyde (0.787 g, 4.37 mmol) in methanol(17 mL, 420 mmol) and Tetrahydrofuran (6 mL, 70 mmol). After 1 hour thesame amount of pyruvaldehyde and 16.0 M of Ammonia in water were addedagain. The mixture was stirred for 2 h, concentrated in vacuum and theresidue partitioned between ethyl acetate and water. The organic extractwas washed with water, brine, dried over MgSO4 and concentrated. Theresidue was purified on 4 g silica column using ethyl acetate gradientin dichloromethane. Weight 0.417 g. MS: 344.9.

Example 359-bromo-2-(1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Ethanedial (0.689 mL, 6.01 mmol) and 16.0 M of Ammonia in water (1.50mL) were added to a9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbaldehyde(550 mg, 1.5 mmol) in Methanol (30.0 mL, 742 mmol) After 1 hour,additional quantity of Ethanedial and ammonia were added and the mixturewas stirred for 4 hours. The mixture then was concentrated in vacuum andpartitioned between 0.5 N HCl and ethyl acetate. The organic extract wasdiscarded, the acidic aqueous basified by careful addition of sat.NaHCO3. The mixture was extracted with ethyl acetate, the organicextracts were washed with water, brine, dried and concentrated. Theresidue was triturated with DCM to produce a precipitate which wascollected, washed with cold DCM and dried to give9-bromo-2-(1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine.MS: (ESI+)=331.2

Example 369-bromo-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

To a solution of9-bromo-2-(1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.237 g, 0.716 mmol) and Cesium Carbonate (0.280 g, 0.859 mmol) inN,N-Dimethylformamide (4.74 mL, 61.2 mmol) was added Isopropyl iodide(0.0859 mL, 0.859 mmol). The reaction was stirred 18 h at 50 C. Thereaction was quenched with water then extracted EtOAc 2×. The crudeproduct was purified to give9-bromo-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine.MS: (ESI+)=373.1

Example 37 methyl 3-hydroxy-4-(1H-imidazol-2-yl)benzoate

4-Formyl-3-hydroxybenzoic acid (5 g, 30 mmol) was suspended in methanol(70 mL), and treated with thionyl chloride (3.29 mL 45 mmol) dropwise.The mixture was heated to reflux overnight. Concentrated to dryness, and50 mL of toluene was added, and concentrated again. The residue wasrecrystallized from ethyl acetate-hexane. A total of 4.8 g (85%) ofmethyl 4-formyl-3-hydroxybenzoate was obtained.

A mixture of methyl 4-formyl-3-hydroxybenzoate (4.8 g, 27 mmol), 40%aqueous solution of ethanedial (11.6 g, 79.93 mmol) and 50% aqueousammonia (6.8 g, 399 mmol) in methanol (50 mL) was stirred for 2 hours orlonger until the reaction is done. The solvent was removed by rotaryevaporation, and the residue was partitioned between ethyl acetate andwater. The mixture was filtered to remove the precipitates. pH wasadjusted to 5-6 by careful addition of 1 N HCl. The aqueous layer wasextracted with EtOAc three times. The combined organic layer was washedwith water, brine and dried over MgSO4. The residue was purified byflash chromatography to yield methyl3-hydroxy-4-(1H-imidazol-2-yl)benzoate as a yellow solid (4 g, 71%)

Example 38 methyl5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate

A mixture of methyl 3-hydroxy-4-(1H-imidazol-2-yl)benzoate (2.2 g, 10mmol), 1,2-dibromoethane (3.12 mL, 36 mmol) and cesium carbonate (13.14g, 40 mmol) in DMF (100 mL) was heated at 90° C. for 12 hours. Themixture was filtered, the mother liquor was concentrated in vacuo, andthe residue was partitioned between water and ethyl acetate. Thesuspension was filtered and the solid was pure byproduct. The organiclayer was washed with water, brine and dried over MgSO4 and concentratedto give crude methyl5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (2 g,80%).

Example 38a 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

To a solution of10-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (9 g, 20mmol) in THF (40 mL) was added Ethylmagnesium bromide in Ethyl ether (22mL) at −20° C. The mixture was allowed to warm to room temperature andin one and half hour the completion was showed by LCMS. The reactionmixture was poured into 10% NH4Cl and extracted by EtOAc. Organic layerwas washed by brine, dried by MgSO4 and concentrated. The crude waspurified urified by Isco chromatography to afford10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. LC/MS (ESI+):m/z 265 (M+H).

Example 38b10-(2-fluoropyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

To 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (140 mg,0.53 mmol) in DMF (20 mL) and water (2 mL) was added2-Fluoropyridine-3-boronic acid (89 mg, 0.632 mml), Potassium acetate(207 mg, 2.11 mmol) and Tetrakis(triphenylphosphine)palladium (30 mg,0.0264 mmol). The reaction mixture was degassed for 5 minutes, andheated at 100° C. overnight. LCMS showed desired product peak. Thereaction was allowed to cool to room temperature, diluted with EtOAc,and filtered through a thin pad of celite. The filtrate was washed withwater followed by brine, dried over MgSO4 and concentrated. The cruderesidue was purified by Prep HPLC to provide10-(2-fluoropyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine.LC/MS (ESI+): m/z 282 (M+H)

Example 38c3-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one

To a solution of10-(2-fluoropyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(100 mg, 0.4 mmol) in DME (4 mL) was added 10% aqueous HCl (4 mL). Thereaction was allowed to stir and heated at 80° C. overnight. Thereaction was allowed to cool to room temperature and concentrated underreduced pressure. The crude was purified by Prep HPLC to provide3-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one.LC/MS (ESI+): m/z 280 (M+H). 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H),8.71 (d, J=2.3, 1H), 7.72-7.50 (m, 1H), 7.47-7.21 (m, 1H), 7.15-6.86 (m,2H), 6.29 (t, J=6.6, 1H), 4.44 (d, J=6.1, 4H).

Example 38d4-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one

Following the procedures of Examples 38a-c,4-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-onewas prepared. LC/MS (ESI+): m/z 280 (M+H). H NMR (500 MHz, DMSO) δ 8.70(d, J=2.5, 1H), 7.59 (dd, J=8.5, 2.5, 1H), 7.45 (d, J=6.8, 1H), 7.35 (s,1H), 7.09 (dd, J=16.9, 4.7, 2H), 6.57-6.36 (m, 2H), 4.47 (dd, J=11.6,5.6, 4H).

Example 38e5-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one

Following the procedures of Examples 38a-c,5-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-onewas prepared. LC/MS (ESI+): m/z 280 (M+H). 1H NMR (500 MHz, DMSO) δ 8.48(s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 7.83 (d, J=10.8, 1H), 7.77 (d,J=8.7, 1H), 7.21 (d, J=8.7, 2H), 6.46 (d, J=9.8, 1H), 4.65 (dd, J=24.3,4.8, 4H).

Example 39 methyl2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate

A mixture of methyl5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (2 g, 8mmol) and NIS (9.2 g, 41 mmol) in DMF was heated at 80° C. overnight.The mixture was diluted with ethyl acetate and water. The thicksuspension was filtered through a glass filter. The solid was washedwith ethyl acetate, then further diluted with THF, and dried over MgSO4.LCMS indicated that this solution contained pure product. The brownsolution was washed with 10% sodium thiosulfate, water, brine dried overMgSO4 and concentrated to small volume. The precipitate was filtered anddried to give methyl2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate(3.4 g, 81% yield).

Example 40 methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate

Fresh ethyl magnesium bromide in ethyl ether (3.0 M 1.1 mL) was addeddropwise to a suspension of methyl2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate(1.1 g, 2.2 mmol) in THF at −15° C. The mixture was stirred andmonitored using LC/MS. After 1 hour, there was no remaining startingmaterial and the reaction was poured into sat. NH4Cl and extracted withEtOAc. The organic extracts were washed with water, brine, dried overMgSO4 and concentrated. At the end of this process, 0.7 g (80%) ofmethyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate wasobtained.

Example 41 methyl2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate

Methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate(740, 2.3 mmol) and copper cyanide (537 mg, 6.9 mmol) were mixed in DMF(8 mL). The reaction was microwaved on 200 watts, 150° C. for 40minutes. The reaction mixture was partitioned between 15% ammonia inwater and EtOAc. The aqueous layer was extracted with EtOAc three times,combined organic extracts were washed with water, brine and dried overMgSO4 to produce 0.46 g (74% yield) of methyl2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate.

Example 42 methyl2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate

Methyl2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate(0.46 g, 1.7 mmol) was stirred with potassium carbonate (469 mg, 3.4mmol), water (1.2 mL) and hydrogen peroxide (408 mg, 6 mmol) in DMSO (7mL) for 4 hours. The mixture was diluted with 70 mL of water andextracted with ethyl acetate. Ethyl acetate solution was washed withwater, 5% Na2S2O3, water, brine, dried over MgSO4 and concentrated undervacuum to give methyl2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate(0.37 g).

Example 439-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

Step 1: 5-bromo-2-(1H-imidazol-2-yl)phenol

4-Bromo-2-hydroxybenzaldehyde (1.0 g, 5 mmol), 40% aqueous solution ofethanedial (3.6 g, 24.87 mmol) and 50% aqueous ammonia (2.5 g) inmethanol (20 mL) was stirred for 2 h or longer until the reaction isdone. The solvent was concentrated by rotary evaporation and the residuewas partitioned between EtOAc and water. The mixture was filtered toremove the precipitate. pH was adjusted to 5-6 by careful addition of 1N HCl. The aqueous layer was extracted with EtOAc three times. Thecombined organic layer was washed with water, brine and dried overMgSO4. Purified by ISCO chromatography (30% EtOAc/DCM) yielded5-bromo-2-(1H-imidazol-2-yl)phenol as yellow solid 0.9 g.

Step 2: 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

A mixture of 5-bromo-2-(1H-imidazol-2-yl)phenol (0.9 g, 4 mmol),1,2-dibromoethane (1.3 mL, 15 mmol) and cesium carbonate (4.9 g, 15mmol) in DMF (20 mL) was heated to 90° C. for 12 h. The mixture waspartitioned between water and ethyl acetate. The organic layer waswashed with water, brine and dried over MgSO4 and concentrated to give9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.8 g).

Step 3:9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

A mixture of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.8 g, 3 mmol) and NIS (1.87 g, 8.3 mmol) in DMF was stirred at roomtemperature for 48 h. The mixture was diluted with ethyl acetate, washedwith 5% sodium bicarbonate, 10% sodium thiosulfate, water and brine andthe organic layer was dried over MgSO4 and concentrated to a solidresidue. Purified by ISCO chromatography (30% EtOAc/Heptane) yielded9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 1.2g.

Step 4: 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

A 3.0 M solution of ethylmagnesium bromide in ethyl ether (1.1 mL) wasadded dropwise to a suspension of9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.1g, 2.2 mmol) in THF at −15° C. The mixture was stirred and followed byLC/MS. After 1 hour, there is no starting material left and the reactionwas poured into sat. NH4Cl and extracted with ethyl acetate. The organicextracts were washed with water, brine, dried over MgSO4 andconcentrated. The crude residue was purified by flash columnchromatography to provide9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine as whitesolid (0.7 g).

Step 5:9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.5 g,3.8 mmol) and bis(triphenylphosphine) palladium(II) chloride (142 mg,0.202 mmol), DMF (45 mL) and hexamethyldisilazane (4.34 mL, 20.6 mmol)were mixed. The entire solution was purged with a CO balloon and sealedwith the CO balloon attached. The reaction flask was heated at 70° C.for 2 h. LC/MS indicated clean conversion. Cooled to room temp andpoured into 1 N HCl (30 mL). Stirred for 5 min and neutralized with sat.aq. NaHCO₃ soln. Extracted three times with EtOAc, dried over MgSO4,filtered and concentrated in vacuo. Triturated with IPA and the solidswere collected after filtration and EtOAc wash. This provided 734 mg(62% yield) of9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide asa tan solid. LC/MS (ESI+): m/z 310 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.36(d, J=8.5, 1H), 7.63 (s, 1H), 7.24 (dd, J=7.2, 4.2, 1H), 7.09-6.99 (m,1H), 4.51-4.36 (m, 4H).

Example 449-bromo-N-formyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (10 g,25.6 mmol) was heated in formamide (200 mL) with Pd(dppf)Cl2 (0.94 g,1.28 mmol) and DMAP (3.13 g, 25.6 mmol) under CO balloon at 70° C. for2.5 h. The mixture was cooled to room temperature, diluted with EtOAcand filtered. The resulting precipitate was dried to obtain9-bromo-N-formyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide(6.7 g, 78%). 1H NMR (DMSO-d6, 400 MHz): δ 11.10 (d, J=9.6 Hz, 1H), 9.21(d, J=9.6 Hz, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.24 (s, 1H), 7.34-7.28 (m,2H), 4.53-4.50 (m, 4H). LC-MS: (ESI, m/z)=336 [M+H]+

Example 468-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid[1-dimethylamino-eth-(E)-ylidene]-amide

To a solution of8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidamide (0.280 g, 0.000909 mol) in toluene (5 mL) was addeddimethylacetamide-dimethylacetal (0.405 mL, 0.00273 mol). The solutionwas stirred at 95° C. for 4 h. The toluene was removed in vacuo to give8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid[1-dimethylamino-eth-(E)-ylidene]-amide. MS(ESI+) 377.1/379.1.

Example 47[5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamicacid tert-butyl ester

Step 1:8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidmethyl ester

8-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (6.000 g,0.01534 mol) followed by palladium acetate (0.1722 g, 0.0007672 mol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.8879 g, 0.001534 mol)were added sequentially to a dry nitrogen-filled flask. Degassedtriethylamine (180 mL, 1.3 mol) and methanol (60 mL) were added, and thereaction mixture was thoroughly purged with a carbon monoxide balloonfor about 3 minutes. Two carbon monoxide balloons were fixed to theflask and the reaction was heated to 50° C. for 3 hours. The reactionwas purged with nitrogen, concentrated in vacuo, and dry loaded ontosilica gel. The crude was purified by flash chromatography (40-100%ethyl acetate in hexanes followed by 5-15% MeOH in DCM) to give8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidmethyl ester (4.242 g) as a light brown solid. MS(ESI+) 323.0/325.0

Step 2:8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid

To a solution of8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidmethyl ester (1.000 g, 0.003095 mol) in tetrahydrofuran (7.50 mL) andwater (4.5 mL) was added lithium hydroxide (0.2964 g, 0.01238 mol). Thereaction was stirred at 45° C. for 2 h. The mixture was acidified topH=1 with 2N HCl. The resulting precipitate was filtered and rinsed withcold water to obtain8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid(860 mg) as an off-white solid. MS(ESI+) 309.0/311.0

Alternatively, to a solution of8-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-enzo[e]azulene (10 g, 25.6mmol) in THF (120 mL) at −78° C. was added nBuLi (19.2 mL, 1.6 M inhexanes, 30.7 mmol) at such a rate that Tmax<−73° C. During the additionthe purple colour faded and a tan precipitate formed. The reactionmixture was stirred at −78° C. for 20 min. CO2 generated from dry-iceand passed over drying silica was bubbled through the reaction for 30min. The temperature rose to −55° C. before dropping back to −78° C. Athick precipitate formed quickly during the addition of CO2. Thereaction was stirred at −78° C. for 1 h. The reaction was quenched bypouring onto 20 mL water (CARE: effervescent). The mixture was allowedto warm to RT. The pH of the mixture was adjusted to ˜pH 8 by additionof saturated aqueous NaHCO3 and the aqueous layer washed with ethylacetate. The aqueous fraction was collected and the pH adjusted to ˜pH 4by addition of AcOH. The precipitate formed was collected by filtration,washed with water and dried in vacuo to give8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidas a beige solid (4.38 g, 55%). 1H NMR (400 MHz, d6-DMSO) 8.31 (1H, d,J=8.5 Hz), 7.98 (1H, s), 7.32 (1H, dd, J=8.5, 2.2 Hz), 7.27 (1H, d,J=2.2 Hz), 4.51-4.47 (4H, m). LCMS: RT=3.67 min, M+H+=309/311 (40%),M+Na+=323/325 (100%). 1H NMR showed product to contain ˜5%8-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid.

Step 3:{[(E)-8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonylimino]-methylthiomethyl}-carbamicacid tert-butyl ester

To a solution of8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid(0.839 g, 0.00271 mol) and oxalyl chloride (2M in DCM, 1.36 mL, 0.002714mol), in methylene chloride (16.70 mL) under nitrogen atmosphere wasadded 1 drop of N,N-dimethylformamide. The solution was stirred at roomtemperature for 2 h.

The reaction was concentrated in vacuo and the acid chloride wasredissolved in methylene chloride (9.0 mL). The solution was addeddropwise to a solution of N-tertbutoxycarbonyl-S-methylpseudothiourea(0.5164 g, 0.002714 mol) and triethylamine (1.173 mL, 0.008414 mol) inmethylene chloride (9.0 mL). The reaction was stirred at roomtemperature for 1.5 h. Methylene chloride and water were added and themixture was extracted 3× with methylene chloride. Saturated sodiumcarbonate was then added and the mixture was extracted with chloroform.The organic layers were combined and concentrated. The product wasredissolved in methylene chloride and methanol and filtered. Thefiltrate was collected, concentrated and dry loaded onto silica gel andpurified by flash chromatography (0-15% MeOH in DCM) to give{[(E)-8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonylimino]-methylthiomethyl}-carbamicacid tert-butyl ester (658 mg) as an off-white solid. MS(ESI+)481.0/483.0

Step 4:[5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamicacid tert-butyl ester

To a solution of{[(E)-8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonylimino]-methylthiomethyl}-carbamicacid tert-butyl ester (0.658 g, 0.00137 mol) in N,N-dimethylformamide(7.50 mL) was added N,N-Diisopropylethylamine (0.9524 mL, 0.005468 mol)then isopropylhydrazine hydrochloride (0.2267 g, 0.002050 mol). Thereaction was stirred at room temperature for 4 h. Water and methylenechloride were added and the mixture was extracted 3× with methylenechloride. The organic layers were combined, dried with MgSO4 andconcentrated. The crude was purified by flash chromatography (0-10% MeOHin DCM) to give[5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamicacid tert-butyl ester (642 mg) a sticky light yellow solid. The materialwas carried forward without any further purification. MS(ESI+)489.1/491.1

Example 488-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene

To a solution of8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid[1-dimethylamino-eth-(E)-ylidene]-amide (0.340 g, 0.000901 mol) inacetic acid (3.0 mL, 0.053 mol) was added isopropylhydrazinehydrochloride (0.1196 g, 0.001082 mol). The reaction was heated to 95°C. for 3 h. The acetic acid was removed in vacuo and the product wasloaded as a solid onto silica and purified by flash chromatography(0-10% MeOH in DCM) to give8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(293 mg) as an orange solid. MS(ESI+) 388.1/390.1

Alternatively,8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenemay be prepared whereby a mixture of 4-bromo-2-fluoro-benzamidinehydrochloride (5.67 g, 22.3 mmol), potassium hydrogen carbonate (8.95 g,89.4 mmol), THF (45 mL) and water (10 mL) was heated to reflux and asolution of2-bromo-1-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-ethanone (5.5 g,22.3 mmol) in THF (15 mL) added dropwise. The reaction mixture washeated at reflux for 18 h before removal of volatile solvent in vacuo.The resultant suspension was filtered and the residue triturated in hotdiethyl ether to give5-[2-(4-Bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-3-methyl-1H-[1,2,4]triazoleas an off-white solid (6.4 g, 79%). ¹H NMR 400 MHz (DMSO-d) δ: 7.97 (1H, t, J=8.30 Hz), 7.81 (1 H, s), 7.76 (1 H, dd, J=10.68, 1.92 Hz), 7.58(1 H, dd, J=8.42, 1.93 Hz), 5.79 (1 H, br, m), 2.26 (3 H, s), 1.44 (6 H,d, J=6.60 Hz).

A suspension of5-[2-(4-bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-3-methyl-1H-[1,2,4]triazole(2.9 g, 7.96 mmol) in toluene (50 mL) was treated with ethylenecarbonate (25 mL) and heated at reflux for 5 h. The cooled reactionmixture was diluted with DCM and passed through a pad of silica elutingwith DCM then 20% methanol in DCM. Methanolic fractions were combinedand concentrated in vacuo to give a pale tan solid. The solid wastriturated in diethyl ether to give2-[2-(4-Bromo-2-fluoro-phenyl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanolas a white solid (2.3 g, 71%). LCMS: RT=2.85 min, [M+H]+=408/410. 1H NMR400 MHz (CDCl3) δ: 8.16 (1 H, s), 7.67-7.20 (3 H, m), 5.83 (1 H, m),4.05 (2 H, t, J=5.10 Hz), 3.92 (2 H, t, J=5.10 Hz), 2.44 (3 H, s), 1.50(6 H, d, J=6.65 Hz).

A suspension of2-[2-(4-bromo-2-fluoro-phenyl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol(2.3 g, 5.6 mmol) in DMF (50 mL) was treated with sodium hydride (60%dispersion, 247 mg, 6.2 mmol) portionwise over 5 min and the mixturestirred at RT for 1 h. The reaction was quenched by the slow addition ofwater (200 mL). The precipitate formed was filtered off, washed withwater to give8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneas a white solid (1.64 g, 53%). LCMS: RT=3.43 min, [M+H]+=388/390. 1HNMR 400 MHz (CDCl3) δ: 8.37 (1 H, d, J=8.61 Hz), 7.70 (1 H, s),7.26-7.25 (2 H, m), 5.87-5.86 (1 H, m), 4.50-4.48 (2 H, m), 4.46-4.42 (2H, m), 2.42 (3 H, s), 1.57 (6 H, d, J=6.64 Hz)

Example 49 9-Bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene

Step 1: 7-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one

To a stirred solution of 5′-bromo-2′-hydroxyacetophenone (10 g, 46.5mmol) in methyl ethyl ketone (100 mL) was added K2CO3 (13.5 g, 97.7mmol) followed by 1,2-dibromoethane (20 mL, 232.5 mmol). The reactionmixture was heated at a mild reflux temperature for 16 h then cooled toroom temperature. The reaction mixture was filtered and thenconcentrated in vacuo. The resultant residue was dissolved in diethylether/ethyl acetate (4:1, 500 mL) and the precipitated solid was removedby filtration. The filtrate was washed with 2 N NaOH (100 mL) and theorganic portion was dried over Na2SO4 and concentrated in vacuo to give1-[5-bromo-2-(2-bromo-ethoxy)-phenyl]-ethanone (8.07 g, 55%) which wasused in the subsequent step without further purification.

To a slurry of NaH (60% dispersion in mineral oil) (1.48 g, 37.1 mmol)in THF (50 mL) at room temperature was added[5-bromo-2-(2-bromo-ethoxy)-phenyl]-ethanone (8.07 g, 25.1 mmol). Thereaction mixture was slowly heated to reflux and allowed to stir for 20h. The solvent was removed in vacuo and the residue subjected to flashchromatography (SiO2, 4:1 ethyl acetate/petroleum ether) to give7-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one as a yellow oil (4.22 g,70%). 1H NMR (CDCl3) δ 2.15-2.29 (2H, m), 2.89 (2H, t, J=7.0 Hz), 4.24(2H, t, J=6.6 Hz), 6.97 (1H, d, J=8.8 Hz), 7.50 (1H, dd, J=2.6, 8.1 Hz),7.87 (1H, d, J=2.6 Hz).

Step 2:7-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one

7-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (10.0 g, 41.5 mmol) indimethylformamide dimethylacetal (100 mL) was heated at 110° C. for 18h. The reaction was allowed to cool to room temperature and cyclohexane(100 mL) was added. The resulting solid precipitate was collected byfiltration, washed with cyclohexane and then dried under vacuum at 40°C. to yield7-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-oneas yellow crystals (8.19 g, 67%). ¹H NMR δ (ppm)(CDCl3): 7.83 (1 H, d,J=2.59 Hz), 7.74 (1 H, s), 7.46 (1 H, dd, J=8.51, 2.58 Hz), 6.88 (1 H,d, J=8.52 Hz), 4.27-4.19 (2 H, m), 3.14 (6 H, s), 2.76-2.69 (2 H, m).

Step 3: 9-Bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene

To a suspension of8-bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one(8.19 g, 27.7 mmol) in ethanol (100 mL) was added powdered hydrazinedihydrochloride (5.81 g, 55.3 mmol) at room temperature and the mixturestirred for 3 h. The reaction mixture was concentrated to near drynessin vacuo and isopropyl alcohol (200 mL) and water (100 mL) added. Theresultant mixture was heated at reflux for 3 h them allowed to cool toroom temperature. The mixture was concentrated in vacuo to remove thevolatile solvent then diluted to 400 mL with water. The resulting solidprecipitate was collected by filtration, washed with water and driedunder vacuum at 40° C. to yield9-Bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene as a pale yellowsolid (7.8 g, 106%). ¹H NMR δ (ppm)(CDCl3): 8.27 (1 H, d, J=2.45 Hz),7.59 (1 H, s), 7.32 (1 H, dd, J=8.64, 2.41 Hz), 6.94 (1 H, d, J=8.64Hz), 4.34-4.28 (2 H, m), 3.15-3.09 (2 H, m).

Example 50 8-Bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene

Step 1:8-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one

8-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (5.0 g, 20.7 mmol) indimethylformamide dimethylacetal (15 mL) was heated at 110° C. for 18 h.The reaction was allowed to cool to room temperature and cyclohexane (20mL) was added. The resulting solid precipitate was collected byfiltration, washed with cyclohexane and then dried under vacuum at 40°C. to yield8-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-oneas yellow crystals (5.32 g, 86%). ¹H NMR δ (ppm)(CDCl3): 7.73 (1 H, s),7.61 (1 H, d, J=8.29 Hz), 7.29 (1 H, dd, J=8.29, 1.94 Hz), 7.18 (1 H, d,J=1.91 Hz), 4.28-4.21 (2 H, m), 3.14 (6 H, s), 2.77-2.70 (2 H, m).

Step 2: 8-Bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene

To a suspension of8-bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one(5.32 g, 17.9 mmol) in isopropyl alcohol (50 mL) was added powderedhydrazine dihydrochloride (3.77 g, 35.9 mmol) at room temperature, thenthe mixture stirred for 2 h. The reaction mixture was diluted with water(20 mL) and then heated at 100° C. for 2 h before cooling to roomtemperature. The reaction mixture was concentrated in vacuo to removethe volatile solvent. The resulting suspension was filtered and thefiltrate washed with water and dried under vacuum at 40° C. to yield8-Bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene as a pale yellowsolid (4.28 g, 90%). ¹H NMR δ (ppm)(DMSO-d): 8.07 (1 H, d, J=8.52 Hz),7.64 (1 H, s), 7.30-7.24 (1 H, m), 7.21 (1 H, d, J=2.07 Hz), 4.24 (2 H,dd, J=5.63, 4.50 Hz), 3.00 (2 H, t, J=5.09 Hz).

Example 518-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidamide

To a solution of8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid(8.27 g, 26.7 mmol), EDCI (6.66 g, 34.8 mmol), HOBt (4.69 g, 34.8 mmol)and ammonium chloride (4.29 g, 80.2 mmol) in DMF (80 mL) was addedtriethylamine (7.49 mL, 53.5 mmol) and the reaction mixture stirred at45° C. for 1.5 h. The reaction mixture was concentrated in vacuo and theresidue triturated with water (250 mL). The precipitated product wascollected by filtration and dried in vacuo at 45° C. for 16 h to give8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidamide as a buff coloured solid (7.67 g, 93%). 1H NMR (400 MHz, d6-DMSO)8.40 (1H, d, J=8.7 Hz), 7.80 (1H, s), 7.42 (1H, br s), 7.32 (1H, dd,J=8.7, 2.0 Hz), 7.27 (1H, d, J=2.1 Hz), 7.15 (1H, br s), 4.50-4.46 (4H,m). LCMS: RT=3.07 min, M+H+=308/310. 1H NMR showed product to contain 5%8-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidamide.

Alternatively, a solution of8-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (10.00 g,0.02558 mol) in N,N-Dimethylformamide (250 mL) was thoroughly degassedwith N2. Bis(triphenylphosphine)palladium(II) chloride (0.807 g, 0.00115mol) was added followed by Hexamethyldisilazane (21.58 mL, 0.1023 mol).The solution was flushed with CO for 2 minutes and then sealed with a COballoon attached. The reaction was heated to 70° C. for 2.5 hours.Methylene chloride and saturated NH4Cl were added and the mixture wasextracted 4 times with methylene chloride. The organic phases werecombined, dried with MgSO4 and concentrated. A small amount ofisopropanol was added and the mixture was triturated overnight. Themixture was filtered to yield 5.97 g (76% yield) of8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidamide as a fine brown powder. MS(ESI+) 308.0/310.0

Example 528-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene

Step 1:8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid1-dimethylamino-meth-(Z)-ylideneamide

To a suspension of8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidamide (7.67 g, 24.9 mmol) in dioxane (150 mL) was added DMF-DMA (9.92mL, 74.7 mmol) and the reaction mixture heated at 100° C. for 1 h.During the reaction the solids dissolved to give a brown solution. Thereaction mixture was concentrated in vacuo and the solid residuetriturated with diethyl ether (˜150 mL). The product was collected byfiltration and dried in vacuo at 45° C. for 3 h to yield8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid1-dimethylamino-meth-(Z)-ylideneamide as a buff coloured solid (8.52 g,94%). 1H NMR (400 MHz, d6-DMSO) 8.56 (1H, s), 8.34 (1H, d, J=8.6 Hz),7.96 (1H, s), 7.32 (1H, dd, J=8.6, 2.0 Hz), 7.26 (1H, d, J=2.1 Hz),4.51-4.46 (4H, m), 3.16 (3H, s), 3.08 (3H, s). 1H NMR showed product tocontain 5%8-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid1-dimethylamino-meth-(Z)-ylideneamide.

Step 2

To a solution of8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid1-dimethylamino-meth-(Z)-ylideneamide in acetic acid was addedisopropylhydrazine hydrochloride. The reaction was heated to 95° C. for3 h. The acetic acid was removed in vacuo and the product was loaded asa solid onto silica and purified by flash chromatography (0-10% MeOH inDCM) to give8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid1-dimethylamino-meth-(Z)-ylideneamide.

Example 531-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazoleand1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazole

Isopropylmagnesium chloride (iPrMgCl—LiCl, 4.3 mL of 1.3 M) in THF wasadded dropwise to a solution of4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazole (1.50 g,4.66 mmol, mixture of regioisomers) in tetrahydrofuran (20 mL, 0.3 mol)at 0° C. The reaction mixture was stirred at 0° C. for 1 hour.Tributyltin chloride (1.64 mL, 6.05 mmol) was added and the mixturewarmed to room temperature and stirred overnite. The reaction mixturewas rotovapped and quenched with water, diluted with dichloromethane andfiltered over celite. The aqueous layer was extracted and the crude,concentrated organic purified by flash column chromatography 50-100%ethylacetate in hexanes. NMR showed a 2:1 ratio of1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazoleand1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazole(assumed by literature references of similar imidazole substitutions).Regioisomers were not separated.

Example 54 1-(4-bromo-1H-imidazol-1-yl)-2-methylpropan-2-ol and1-(5-bromo-1H-imidazol-1-yl)-2-methylpropan-2-ol

To a suspension of 4-bromo-1H-imidazole (1.0 g, 6.8 mmol) andisobutylene oxide (0.665 mL, 7.48 mmol) in methanol (0.331 mL, 8.16mmol) was added cesium carbonate (0.63 g, 1.9 mmol). The reactionmixture was heated in a sealed vessel cautiously at 110° C. for 1.5 hrs.The reaction was cooled to room temperature, diluted with diethyletherand washed 2 times with water. The organics were washed with brine,dried over magnesium sulfate and concentrated in vacuo to give a whitesolid which was flash purified with 100% ethyl acetate to get the twodistinct intermediates. The major regioisomer was1-(4-bromo-1H-imidazol-1-yl)-2-methylpropan-2-ol (0.8 g, 54% yield, M+1220) while the minor regioisomer was1-(5-bromo-1H-imidazol-1-yl)-2-methylpropan-2-ol (0.32 g, 21% yield M+1220).

Example 55N,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine

To a solution of4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (250 mg,1.29 mmol) and sodium hydride (61.8 mg, 2.58 mmol) in tetrahydrofuran at0° C. was added 2-bromo-N,N-diethylethanamine (558 mg, 2.58 mmol). Thereaction was allowed to warm up to room temperature and was monitored byLCMS. After 90 minutes there was still no reaction and potassium iodide(1.71 g, 10.3 mmol) was added and the reaction was heated at 50° C.overnight. The reaction mixture was diluted with a large volume of ethylacetate and water and partitioned. The organic layer containing theproduct was washed with brine and concentrated in vacuo to give clearthick oil confirmed by LCMS to be 100% pureN,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine(340 mg, yield 90%, M+1 294.2)

Example 561-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(trimethylstannyl)-1H-imidazole

Step 1: 2,4,5-triiodo-1H-imidazole

To a mixture of 1H-Imidazole (50 g, 0.73 mol) in DMF (200 mL) was addedNIS (328 g, 1.46 mol) portionwise, the reaction mixture was stirred atroom temperature for 4 hours. The reaction mixture was poured in sat.Na2CO3 solution, filtered, the residue was washed with water and driedto give 150 g of 2,4,5-triiodo-1H-imidazole (Yield=46%).

Step 2: 4-iodo-1H-imidazole

2,4,5-triiodo-1H-imidazole was reacted with Na2SO3 in DMF (250 mL) andstirring at 110° C. for over night under N2 atmosphere. The reactinmixture was filtered, the filtrate was concentrated and poured intowater, then extracted with EtOAc, the organic was washed with water,dried over Na2SO4, concentrated and purified by silica gel column togive 4-iodo-1H-imidazole (Yield=55%). LC-MS: m/z=195 [M+H+]

Step 3: 1-(4-iodo-1H-imidazol-1-yl)-2-methylpropan-2-ol

A mixture of 4-iodo-1H-imidazole, Cs2CO3 in 2,2-dimethyl oxirane wasstirred at 120° C. for 20 min under irradiation with microwave. Thereaction mixture was concentrated, and purified to give1-(4-iodo-1H-imidazol-1-yl)-2-methylpropan-2-ol (Yield=71%). LC-MS:m/z=266 [M+H+] 1H NMR (CDCl₃, 400 MHz): δ7.36 (s, 1 H), 7.06 (s, 1 H),3.84 (s, 2 H), 1.22 (s, 6 H).

Step 4:1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-1H-imidazole

1-(4-iodo-1H-imidazol-1-yl)-2-methylpropan-2-ol was dissolved in DCm andlutidine was added dropwise at 0° C. The mixture was stirred at 0° C.for 30 min then tert-butyldimethylsilyl triflate (TBSOTf) was addeddropwise. The mixture was warmed to room temperature and stirred forabout an hour, then quenched with 30% acetic acid, extractedethylacetate, dried, and concentrated to give1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-1-imidazole(Yield=74%). LC-MS: m/z=381[M+H+]

Step 5:1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(trimethylstannyl)-1H-imidazole

To a mixture of1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-1H-imidazole inDCM was added ethylmagnesium bromide at −78° C. The temperature of themixture was allowed to warm up to about 10° C. slowly and cooled again.Trimethyltin chloride was added dropwise at −78° C. After the addition,the temperature was allowed to slowly warm up to room temperature. Thereaction mixture was pouted into saturate NH4Cl solution, then extractedwith DCM. The organic phase was washed with water twice, dried overanhydrous Na2SO4, and concentrated to give1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(trimethylstannyl)-1H-imidazole(Yield=74%). LC-MS: m/z=419[M+H+]1H NMR (CDCl₃, 400 MHz): δ 7.63 (s, 1H), 7.00 (s, 1 H), 3.79 (s, 2 H), 1.22-1.19 (s, 6 H), 0.86 (s, 9 H),0.27 (s, 6 H), 0.02 (s, 6 H)

Example 572-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Step 1:9-bromo-2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Isopropyl iodide (165 uL, 1.65 mmol) was added to a mixture of 417 mg(1.21 mmol) of9-bromo-2-(4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineand cesium carbonate (538 mg, 1.65 mmol) in 3 ml ofN,N-dimethylformamide. The reaction mixture was stirred at roomtemperature for 18 hours, mixed with water and extracted with ethylacetate. The organic extract was washed with water, brine, dried overMgSO4, concentrated, and purified on 4 g silica column eluting with 4-5%methanol in DCM to give 210 mg of9-bromo-2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine.MS: 387.1.

Step 2

A solution of9-bromo-2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(1.00 g, 0.00258 mol) and potassium acetate (0.758 g, 0.00773 mol) indimethyl sulfoxide (8.5 mL, 0.12 mol;) in a round bottom flask equippedwith a magnetic stir bar was thoroughly purged with nitrogen. Bispinacolester boronate (0.719 g, 0.00283 mol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.210 g, 0.258 mmol) was added and thereaction was heated to 85° C. under inert atmosphere. The reaction wasmonitored by LC/MS and was complete after 6 hr. The mixture waspartitioned between water and methylene chloride and the mixture wasextracted 3× with methylene chloride. The organic phases were combined,dried with MgSO4 and concentrated. The whole was loaded onto silica andpurified by flash chromatography (0-10% MeOH in DCM followed by 100%EtOAC) to give2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(488 mg) as a beige solid. MS(ESI+) 436.2.

Example 589-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene

9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenewas prepared from 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(450 mg, 1.7 mmol) and 5-chloro-1-isopropyl-1H-[1,2,4]triazole (369 mg,2.55 mmol) to give9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azuleneas a white solid (375 mg, 59%). LCMS RT=5.05 min M+H+=374/376

Example 599-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene

9-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenewas prepared similarly to8-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenefrom 5-chloro-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (1.33 g, 6.16mmol) and 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.36g, 5.13 mmol), the crude product was subjected to flash chromatography(SiO2, gradient 0 to 35% ethyl acetate in cyclohexane) to give9-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen(1.42 g, 62%). LCMS RT=4.80 M+H+=444/446.

Example 609-Bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene

Following the procedures in Example 103, 2,4-dichlorophenyl hydrazinehydrochloride was reacted with formamide to give1-(2-Chloro-phenyl)-1H-[1,2,4]triazole as an off-white solid. ¹H NMR δ(ppm)(CDCl3): 8.54 (1 H, s), 8.14 (1 H, s), 7.61-7.54 (2 H, m),7.46-7.39 (2 H, m).

Following the procedure for5-chloro-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole,1-(2-chloro-phenyl)-1H-[1,2,4]triazole was reacted with n-butyllithiumand hexachloroethane to give5-Chloro-1-(2-chloro-phenyl)-1H-[1,2,4]triazole as a white solid. ¹H NMRδ (ppm)(CDCl3): 8.05 (1 H, s), 7.61-7.58 (1 H, m), 7.55-7.48 (1 H, m),7.46-7.43 (2 H, m).

9-Bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenewas prepared similarly to8-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenefrom 5-chloro-1-(2-chloro-phenyl)-1H-[1,2,4]triazole (2.25 g, 10.5 mmol)and 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.9 g, 7mmol), the crude product was subjected to flash chromatography (SiO2,gradient 0 to 60% DCM (+10% ethyl acetate) in cyclohexane) to give9-Bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(1.3 g, 33%). LCMS RT=4.82 M+H+=442/444

Example 619-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene

Step 1: 4-Bromo-1-but-3-ynyloxy-2-nitro-benzene

A mixture of 4-bromo-1-fluoro-2-nitrobenzene (20.0 g, 90 mmol),3-butyn-1-ol (7.0 g, 99.8 mmol) and potassium carbonate (13.8 g, 99.8mmol) in dry DMF (20 mL) was heated with 4 Å molecular sieves for 43 h.The mixture was cooled, diluted with water to approximately 500 mL andextracted three times with ethyl acetate. The combined organic extractswere washed with water and then brine, dried and concentrated in vacuo.The resultant residue was subjected to flash chromatography (SiO2,gradient 5 to 10% ethyl acetate in cyclohexane) to give4-Bromo-1-but-3-ynyloxy-2-nitro-benzene as a yellow solid (17.35 g,71%). NMR showed an impurity (19%) which was not removed at this stage.LCMS: RT=4.41 min, [M+Na]+=292/294.

Step 2: 5-Bromo-2-but-3-ynyloxy-phenylamine

4-Bromo-1-but-3-ynyloxy-2-nitro-benzene (82% pure, 4.22 g, 12.5 mmol)was heated in a mixture of IMS (Industrial Methylated Spirits, 40 mL)and glacial acetic acid (2 mL) at approx. 50° C. until a solution wasformed. Iron powder (5.05 g, 89.8 mmol) and iron (III) chloridehexahydrate (0.56 g, 1.56 mmol) were added and the mixture was heatedunder reflux for 18 h. The cooled mixture was filtered through Celite®,and washed through with ethyl acetate. The filtrate was washed withwater, followed by brine, dried (Na2SO4), filtered and concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 10 to 20% ethyl acetate in cyclohexane) to give5-Bromo-2-but-3-ynyloxy-phenylamine as an orange oil (2.68 g, 89%).LCMS: RT=4.10 min, M+H+=240/242.

Step 3: Chloro-(5-bromo-2-but-3-ynyloxyphenylhydrazono)acetic acid ethylester

2-Chloro-3-oxo-butyric acid ethyl ester (1.94 g, 11.2 mmol) and sodiumacetate (1.45 g, 17.8 mmol) were stirred in IMS (100 mL) to give a clearsolution, then cooled to 0° C. Separately,5-bromo-2-but-3-ynyloxy-phenylamine (2.68 g, 11.2 mmol) in 6Mhydrochloric acid (6.8 mL) was cooled to 0° C. and a solution of sodiumnitrite (0.77 g, 11.2 mmol) in water (11.2 mL) was added dropwise withstirring, keeping the temperature below 5° C. The aqueous acidicsolution was added to the IMS solution, washed in with a little water,keeping the temperature below 5° C. After 1 h at 0-5° C., the mixturewas diluted with water and extracted several times with ethyl acetate.The combined organic extracts were washed with water, dried (Na2SO4),filtered and concentrated in vacuo to giveChloro-(5-bromo-2-but-3-ynyloxyphenylhydrazono)acetic acid ethyl esteras a pale brown solid (3.96 g, 95%). LCMS: RT=4.97 min,[M+Na]+=395/397/399.

Step 4:9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acidethyl ester

A mixture of chloro-(5-bromo-2-but-3-ynyloxyphenylhydrazono)acetic acidethyl ester (3.28 g, 8.78 mmol) and triethylamine (12.2 mL, 88 mmol) indry toluene (900 mL) was heated at gentle reflux (120° C.) for 54 h. Thecooled mixture was filtered, the residue washed with ethyl acetate andthe filtrate concentrated in vacuo. The resultant residue was subjectedto flash chromatography (SiO2, gradient 10 to 15% ethyl acetate incyclohexane) to give9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acidethyl ester as a yellow solid (2.52 g, 85%). LCMS: RT=4.52 min,M+H+=337/339, [M+Na]+=359/361.

Step 5:9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acidamide

9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acidethyl ester (1.51 g, 4.48 mmol) in 2M ammonia/methanol solution (70 mL)was heated in a pressure bomb at approximately 120° C. (externaltemperature) for 30 h, then allowed to cool. The mixture was filteredand concentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 50 to 100% ethyl acetate in cyclohexane)to give9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acidamide as a pale yellow solid (1.11 g, 80%). LCMS: RT=4.00 min,M+H+=308/310, [M+Na]+=330/332.

Step 6:9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid1-dimethylaminomethylideneamide

A mixture of9-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acidamide (1.11 g, 3.60 mmol) and dimethylformamide dimethylacetal (1.44 mL,10.8 mmol) in dry 1,4-dioxane (25 mL) was heated at 100° C. for 2 h,then concentrated in vacuo. The resultant residue was triturated indiethyl ether to give9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid1-dimethylaminomethylideneamide as a yellow solid (1.27 g, 97%). LCMS:RT=3.27 min, M+H+=363/365.

Step 7:9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene

A mixture of9-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid1-dimethylaminomethylideneamide (1.27 g, 3.5 mmol), isopropylhydrazinehydrochloride (0.48 g, 4.37 mmol) and glacial acetic acid (6 mL) washeated at 110° C. for 6.5 h, then cooled and concentrated in vacuo. Theresultant residue was dissolved in aqueous sodium bicarbonate and DCMand the phases were separated. The aqueous phase was extracted severaltimes with DCM, the combined organic extracts dried (MgSO4) andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 30 to 70% ethyl acetate in cyclohexane)to give9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(0.99 g, 76%). LCMS: RT=5.07 min, M+H+=374/376. ¹H NMR δ (ppm)(CDCl3):8.07 (1 H, d, J=2.41 Hz), 7.96 (1 H, s), 7.39 (1 H, dd, J=8.63, 2.43Hz), 7.08 (1 H, d, J=8.63 Hz), 6.91 (1 H, s), 5.73-5.65 (1 H, m), 4.53(2 H, t, J=5.91 Hz), 3.18 (2 H, t, J=5.91 Hz), 1.60 (6 H, d, J=6.62 Hz)

Example 62 9-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene

Following the procedure for9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene,9-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid1-dimethylaminomethylideneamide was reacted with trifluoroethylhydrazine (70% aqueous) to give9-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azuleneas a white solid. LCMS RT=4.49 min, M+H+=414/416.

Example 638-Azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride

Step 1: 3-Azetidine-1-carboxylic acid tert-butyl ester zinc iodide

In a sealed flask were placed zinc dust (276 mg, 4.22 mmol) and CelpureP65 filter agent (60 mg) and the mixture heated at 300° C. under vacuumfor 10 min. The flask was purged with argon and allowed to cool to RT.To the mixture was added DMA (2.4 mL), followed by dropwise addition ofa mixture of chlorotrimethylsilane (TMSCl) and 1,2-dibromoethane (84 μL,7:5 v:v), causing a slight exotherm and a small amount of effervescence.The reaction mixture was aged at RT for 15 minutes before the dropwiseaddition of 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (0.96 g,3.38 mmol) as a solution in DMA (2 mL). The reaction mixture was stirredat RT for 1.5 h before being filtered to give 3-Azetidine-1-carboxylicacid tert-butyl ester zinc iodide as a colourless solution in DMA.

Step 2:3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylicacid tert-butyl ester

A solution of8-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(1 g, 2.25 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (183 mg, 0.22 mmol) and copper (I) iodide (56 mg,0.29 mmol) in DMA (10 mL) was degassed by vacuum purging then bubblingargon through the mixture (×3). To the dark red mixture was added3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide (1.17 g, 3.38mmol) as a solution in DMA (4.4 mL) and the mixture heated at 85° C. for2 h. During the reaction the mixture turned green, then pale orangebefore finally turning black. The reaction mixture was diluted withwater (20 mL) and ethyl acetate (20 mL) and the mixture filtered throughCelite®. The organic portion of the filtrate was separated and theaqueous extracted with ethyl acetate (2×20 mL). The combined organicfractions were washed with brine (100 mL), dried (MgSO4) and thenconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0 to 100% ethyl acetate in cyclohexane)to give3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylicacid tert-butyl ester as a yellow oil (1.1 g, 94%). LCMS: RT=4.81 min,M+H+=521 (100%), M+H+-OtBu=465 (60%), M+H+-Boc=421 (20%).

Step 3:8-Azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride

3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylicacid tert-butyl ester (1.1 g, 2.11 mmol) was dissolved in hydrochloricacid in dioxane (10 mL, 4N) and the reaction stirred at RT for 1 h.After approximately 5 min a thick white precipitate formed. The reactionwas concentrated in vacuo to yield8-Azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride as a yellow solid (1.0 g, 100%). LCMS: RT=3.00 min,M+H+=421.

Example 648-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride

Step 1:3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester

3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester was prepared similarly to3-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylicacid tert-butyl ester from8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azuleneand 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide. LCMS:RT=4.85 min, M+H+=451 (40%), M+H+-OtBu=395 (100%), M+H+-Boc=351 (10%).

Step 2:8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride

8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride was prepared similarly to8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride from3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester. LCMS: RT=2.86 min, M+H+=351 (20%), M+H+-iPr=308(100%).

Example 658-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride

Step 1:3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester

3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester was prepared similarly to3-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylicacid tert-butyl ester from8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneand 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide. LCMS:RT=4.61 min, M+H+=451.

Step 2:8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride

8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride was prepared similarly to8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride from3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester. LCMS: RT=2.44 min, M+H+=351

Example 662-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt

Step 1:4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester was prepared similarly to3-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylicacid tert-butyl ester from8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(3.0 g, 8.0 mmol) and 4-piperidine-1-carboxylic acid tert-butyl esterzinc iodide (12 mmol) (prepared similarly to 3-azetidine-1-carboxylicacid tert-butyl ester zinc iodide) to give4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (1.2 g, 31%). LCMS: RT=5.06 min, M+H+=479

Step 2:2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt

To a solution of4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (1.2 g, 2.51 mmol) in DCM (12 mL) was added TFA (8mL) and the reaction mixture stirred at RT for 1 h. The reaction mixturewas concentrated in vacuo, the residue tirutrated in diethyl ether togive2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt as a grey solid (1.34 g, 100%). LCMS: RT=2.88min, M+H+=379

Alternatively,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride can be prepared whereby8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(2.1 g, 5.4 mmol), 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acidpinacol ester (2.59 g, 8.3 mmol) and potassium carbonate (1.92 g, 13.9mmol) were mixed with DMF (13 mL) and purged with argon. PdCl2dppf.DCM(310 mg, 0.42 mmol) was added, purging repeated and the mixture heatedto 80° C. for 18 h. After cooling the reaction mixture was filteredthrough Celite®, washing with ethyl acetate, and the filtrateconcentrated in vacuo. The residue was partitioned between ethyl acetateand water, the organic layer separated, dried (Na2SO4), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0 to 2% methanol in ethyl acetate) togive4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (2.56 g, 96%). LCMS RT=4.79, [M+H]+=477. 1H NMR400 MHz (CDCl3) δ: 8.45 (1 H, d, J=8.46 Hz), 7.89 (1 H, s), 7.73 (1 H,s), 7.19 (1 H, dd, J=8.37, 1.80 Hz), 7.04 (1 H, d, J=1.87 Hz), 6.15 (1H, s), 6.04-5.96 (1 H, m), 4.51-4.43 (4 H, m), 4.09 (2 H, d, J=3.68 Hz),3.64 (2 H, t, J=5.64 Hz), 2.52 (2 H, s), 1.59 (6 H, d, J=6.63 Hz), 1.49(9 H, s)

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester was treated with hydrochloric acid to give2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride. ¹H NMR 400 MHz (DMSO-d) δ: 9.08 (2 H, s), 8.37 (1 H, d,J=8.30 Hz), 8.18 (1 H, s), 8.07 (1 H, s), 7.06 (1 H, dd, J=8.35, 1.80Hz), 6.91 (1 H, d, J=1.80 Hz), 5.85 (1 H, m), 4.53 (4 H, m), 3.35 (2 H,d, J=12.46 Hz), 2.98 (2 H, m), 2.87 (1 H, m), 1.93 (4 H, m), 1.50 (6 H,d, J=6.57 Hz)

Example 672-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride

Step 1:4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester was prepared similarly to4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester from9-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(1.55 mg, 1.13 mmol) to give the title compound as a colourless gum(1.47 g, 77%). LCMS RT=5.01 min, M+H+=547

Step 2:2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride was prepared similarly to9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulenefrom4-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (2.06 g, 3.77 mmol) to give the title compound asa white solid (1.15 g, 62%). LCMS RT=3.04 min, M+H+=449

Example 68

(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-4-yl)-methanolhydrochloride

Step 1:4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidine-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester

To a solution of dicyclohexylamine (291 L, 1.463 mmol) in anhydroustoluene (3 mL) was added 2.5M n-butyllithium in hexanes (563 L, 1.575mmol) dropwise at RT under nitrogen. After complete addition the mixturewas stirred at RT for 10 min then ethyl N-Boc-piperidine-4-carboxylate(305 L, 1.24 mmol) was added drop wise at RT and the mixture was stirredfor 30 min. The mixture was added to9-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(500 mg, 1.13 mmol), di(dibenzylideneacetone)-palladium (35 mg, 0.06mmol), tri-tert-butylphosphonium tetrafluoroborate (17.4 mg, 0.06 mmol)at RT under nitrogen then heated to 100° C. After heating for 17 hr themixture was allowed to cool to RT and subjected to flash chromatography(SiO2, gradient 0 to 50% ethyl acetate in cyclohexane) to afford thetitle compound (200 mg, 29%). LCMS RT=4.93 min, M+H+=621.

Step 2:(4-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-4-yl)-methanolhydrochloride

To a solution of4-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidine-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester (200 mg, 0.323 mmol) in anhydrousTHF (10 mL) at 0° C. under nitrogen was added 1M lithium aluminumhydride in THF (485 L, 0.485 mmol) dropwise. The mixture was stirred at0° C. for 15 min then allowed to warm to RT. After 60 min additional 1Mlithium aluminium hydride in THF (485 L, 0.485 mmol) was added andstirring continued. After 2 h the mixture was cooled to 0° C. andcarefully quenched with saturated NH4Cl solution. The mixture wasextracted with DCM and the organic layer washed with water then brine,dried (Na2SO4), and the solvents removed in vacuo. The resultant residuewas dissolved in DCM (10 mL) and treated with 4N HCl in dioxane (2 mL)at RT. After stirring for 5 h the solvent was removed in vacuo, thesolid triturated with diethyl ether and collected by filtration toafford the title compound (97 mg, 58%). LCMS RT=2.84 min, M+H+=479

Example 692-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehyde

Step 1:2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid methyl ester

A suspension of9-bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(2.18 g, 5.28 mmol), molybdenum hexacarbonyl (696 mg, 2.64 mmol),trans-di(mu-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II)(240 mg, 0.24 mmol), tri-tert-butylphosphonium tetrafluoroborate (156mg, 0.52 mmol) and DBU (792 μL, 5.28 mmol) in methanol (15 mL) anddioxane (15 mL) was degassed, then heated at 150° C. for 30 min usingmicrowave irradiation. The reaction mixture was diluted with ethylacetate (20 mL), filtered and the filtrate concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient30 to 60% ethyl acetate in cyclohexane) to yield the title compound(1.02 g, 49%). ¹H NMR δ (ppm)(CDCl3): 8.69 (1 H, d, J=2.12 Hz), 8.03 (1H, s), 7.96 (1 H, dd, J=8.48, 2.12 Hz), 7.22 (1 H, d, J=8.50 Hz), 6.94(1 H, s), 5.57 (2 H, dd, J=16.24, 8.12 Hz), 4.62-4.56 (2 H, m), 3.94 (3H, s), 3.29-3.23 (2 H, m).

Step 2:2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid

To a solution of2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid methyl ester (553 mg, 1.4 mmol) in dioxane (12.5 mL) and water(12.5 mL) was added lithium hydroxide (67 mg, 2.8 mmol) and the reactionmixture stirred at RT for 2 h. The reaction mixture was concentrated invacuo to remove the dioxane and the resultant solution acidified to pH 1by the addition of HCl (12 N). The precipitate formed was collected byfiltration, washed with water and dried in vacuo at 40° C. to give thetitle compound (519 mg, 98%). LCMS: RT=4.04 min, M+H+=380

Step 3:{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-methanol

To a solution of2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid methyl ester (393 mg, 1 mmol) in THF (10 mL) at −70° C. was addedDIBAL (3 mL, 1 M solution in toluene, 3 mmol) and the reaction mixturestirred at 0° C. for 1 h. The reaction mixture was diluted with methanol(5 mL), then with saturated aqueous sodium potassium tartrate solution.The resultant mixture was extracted with ethyl acetate (3×20 mL), thenthe combined organic fractions dried (MgSO4) and concentrated in vacuoto give the title compound (370 mg, 100%).

Step 4:2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehyde

To a solution of{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-methanol(370 mg, 1 mmol) in DCM (20 mL) was added Dess-Martin periodinane (467mg, 1.1 mmol) and the reaction mixture stirred at RT for 30 minutes. Thereaction mixture was diluted with DCM (20 mL) and the solution washedwith sodium hydroxide solution (1 M, aqueous). The organic layer wasseparated, dried (MgSO4) and then concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0 to 90%ethyl acetate in cyclohexane) to yield the title compound as a whitesolid (253 mg, 70%). LCMS: RT=4.10, M+H+=364

Example 702-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid

Step 1:2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid methyl ester

Following Example 69,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid methyl ester was prepared from9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(0.99 g, 2.65 mmol). The reaction mixture was diluted with ethyl acetate(20 mL), filtered and the filtrate concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 50 to 100%ethyl acetate in cyclohexane) to give the title compound (0.32 g, 34%).LCMS: RT=4.73, M+H+=354.

Step 2:[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-methanol

Following Example 69,[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-enzo[e]azulen-9-yl]-methanolwas prepared from2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid methyl ester (0.50 g, 1.42 mmol) to give the title compound (360mg, 78%). LCMS: RT=3.81, M+H+=326.

Step 3:2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehyde

Following Example 69,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehydewas prepared from[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-methanol(360 mg, 1.11 mmol). The reaction mixture was diluted with DCM (20 mL)and the solution washed with sodium hydroxide solution (1 M, aqueous).The organic layer was separated, dried (MgSO4) and concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO2, 100% ethyl acetate) to yield the title compound as a white solid(410 mg, 114%). LCMS: RT=4.15, M+H+=324.

Step 4:2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid

Following Example 69,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid was prepared from2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid methyl ester (720 mg, 2.04 mmol). The reaction mixture wasconcentrated in vacuo to remove dioxane and the resultant solutionacidified to pH 1 by the addition of HCl (12 N). The precipitate thatformed was collected by filtration, washed with water and dried in vacuoat 50° C. to give the title compound (584 mg, 84%). LCMS: RT=4.61 min,M+H+=340.

Example 722-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid

Step 1: methyl2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate

To a solution of 1-(2-chlorophenyl)-1H-imidazole (0.133 g, 0.743 mmol;)in tetrahydrofuran (5.43 mL, 66.9 mmol;) at −78° C. was added 1.60 M ofn-Butyllithium in Hexane (0.464 mL) dropwise. The reaction mixture wasstirred at −78° C. for 1 h then 0.50 M of Zinc dichloride inTetrahydrofuran (1.48 mL) was added. The reaction mixture was warmed toRT30 min then added Tetrakis(triphenylphosphine)palladium(0) (0.0780 g,0.0675 mmol;), solution of methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate(0.250 g, 0.675 mmol;) in 2 ml THF. The reaction was reflux for 2 hfollowed by treating with additional 0.50 M of Zinc dichloride inTetrahydrofuran 2.2 ml and refluxed 3 h. The mixture was diluted withEtOAc then washed with sat. Na2CO3, and brine. The organic layer wasdried over Na2SO4, concentrated in vacuo. The crude product, methyl2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate,was purified by chromatography. MS: (ESI+)=421.2

Step 2:2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid

To a solution of methyl2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate(0.100 g, 0.238 mmol) in tetrahydrofuran (5.56 mL, 68.5 mmol) and Water(5.56 mL, 308 mmol) was added Lithium hydroxide, monohydrate (0.0399 g,0.950 mmol). The reaction mixture was stirred at rt o/n. The reactionmixture was concentrated. The reaction mixture was acidified with 1M HClthen extracted with DCM (3×). The combined organics were dried overNa2SO4, filtered and concentrated to give2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid. MS: (ESI+)=407.2

Example 7410-bromo-2-(1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Step 1:10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbaldehyde

10-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine wasformylated to give10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbaldehyde.Yield 84%. MS: 293.1

Step 2

10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbaldehydewas coupled with ethanedial in the presence of ammonia to give10-bromo-2-(1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine.

Yield 37%. MS: 331.0

Example 82 1-(2-bromoethoxy)-2-nitrobenzene 82

To 2-nitrophenol (25.0 g, 0.180 mol) in sodium hydroxide (14.4 g, 359mmol) and Water (6.0 mL, 330 mmol) in a 500 mL flask at 107° C. with areflux condenser was added 1,2-dibromoethane (61.9 mL, 719 mmol), andthe flask was heated at 107° C. for three days (FIG. 18). Then, theproduct was extracted twice with 100 mL DCM, washed with 2M NaOH andbrine, dried with sodium sulfate, and concentrated. Silica gelchromatography eluting with hexanes and ethyl acetate provided thebromide 82 in 63% yield. 1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J=8.4, 1.6Hz, 1H), 7.53 (td, J=8.1, 1.6 Hz, 1H), 7.12-7.01 (m, 2H), 4.45-4.34 (m,2H), 3.67 (t, J=6.5 Hz, 2H), according to: WO 2002076926

Example 83 3-(2-nitrophenoxy)propanenitrile 83

To sodium cyanide (0.398 g, 8.13 mmol) in dimethyl sulfoxide (29.0 mL,409 mmol) at 45° C. was added bromide 84 (2.00 g, 8.13 mmol) in oneportion, and the reaction was stirred for 4 hours at 70° C. (FIG. 18).Then, the reaction was extracted with ethyl acetate, and the organiclayers were dried with sodium sulfate, and concentrated. Silica gelchromatography eluting with hexanes and ethyl acetate provided thenitrile 83 in 43% yield. 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J=8.1, 1.7Hz, 1H), 7.62-7.55 (m, 1H), 7.19-7.13 (m, 1H), 7.11 (dd, J=8.4, 0.8 Hz,1H), 4.36 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), according to Vitaleet al (1994) Anales de la Asociacion Quimica Argentina 82(1):19-23.

Example 84 3-(2-aminophenoxy)propanenitrile 84

To palladium (0.00748 g, 0.0702 mmol) in a 50 mL flask with stirbar wasadded ethyl acetate (11.7 g, 133 mmol) under nitrogen, and then nitrile83 (0.675 g, 3.51 mmol) was added (FIG. 18). The flask was fitted with aballoon containing hydrogen, and the nitrogen inlet was removed. Thereaction was stirred vigorously for 4 hours, and then was filteredthrough celite, washing with ethyl acetate. The product 84 required nofurther purification, 98% yield. 1H NMR (500 MHz, CDCl3) δ 6.85-6.77 (m,1H), 6.74-6.62 (m, 3H), 4.08 (t, J=6.1 Hz, 2H), 3.94-3.74 (m, 2H), 2.72(t, J=6.1 Hz, 2H). LRMS m/z Calcd. for C9H10N2O: 162.07931, found: 163.1[M+1].

Example 85 E/Z)-Methyl2-chloro-2-(2-(2-(2-cyanoethoxy)phenyl)hydrazono)acetate 85

To aniline 84 (1.65 g, 10.2 mmol) in acetic acid (6.80 mL, 120 mmol) and2 M of Hydrogen chloride in water (13.59 mL), then sodium nitrite(1.0290 g, 14.914 mmol;) was added while stirring vigorously at 0° C.(FIG. 18). After 20 minutes, 2-chloroacetoacetate methyl ester (1.5317g, 10.173 mmol) was added dropwise via syringe and the mixture waswarmed to room temperature over 5 hours. Then, the organic layer wasextracted twice with 100 mL diethyl ether and dried with sodium sulfate,and concentrated. The crude product 85 was taken forward for next step.LRMS m/z Calcd. for C12H12ClN3O3 : 281.05672, found: 282.1 [M+1].

Example 86 Methyl4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylate 86

To chlorohydrazone 85 (2.87 g, 10.2 mmol) in a 200 mL flask was added1,4-dioxane (100 mL) and silver carbonate (4.22 g, 15.3 mmol) undernitrogen (FIG. 18). The flask was fitted with a reflux condenser, andwrapped in tin foil (to keep in the dark). Next, the reaction wasrefluxed while stirring for 4 hours. Then, the reaction was filtered,concentrated, and purified by silica gel chromatography to provide ester86 in 7% yield over two steps. 1H NMR (500 MHz, CDCl3) δ 8.19 (dd,J=8.2, 1.4 Hz, 1H), 7.31 (td, J=8.0, 1.6 Hz, 1H), 7.25-7.20 (m, 1H),7.18 (dd, J=8.1, 1.3 Hz, 1H), 4.50 (t, J=5.7 Hz, 2H), 4.03 (s, 3H), 3.50(t, J=5.7 Hz, 2H). LRMS m/z Calcd. for C12H11N3O3: 245.08004, found:246.1 [M+1].

Example 874,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxamide 87

Ester 86 (0.166 g, 0.677 mmol) was dissolved in 3:2:1 THF:MeOH:H2O (31.2mL), treated with 4 N aqueous lithium hydroxide (1.32 mL), and themixture was stirred for 30 min at 25° C. (FIG. 18). The reaction wasquenched with 1 N aq. HCl (20 mL) and the solution was extracted threetimes with 20 mL EtOAc. The combined organic extracts were dried withsodium sulfate, and concentrated to give crude4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylicacid which was taken forward to the next step. LRMS m/z Calcd. forC12H9N3O3: 231.06439, found: 232.1 [M+1].

To crude4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylicacid (0.177 g) in N,N-dimethylformamide (1.55 mL, 20.0 mmol) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.761 g, 2.00 mmol) and6-chloro-1-hydroxybenzotriazole (0.339 g, 2.00 mmol) (FIG. 18). Thereaction was stirred vigorously, and to the reaction was added ammoniumchloride (0.285 g, 5.34 mmol). Then, N,N-diisopropylethylamine (0.465mL, 2.67 mmol) was added after 10 minutes. After 3 hours the reactionwas taken to dryness. Preparative HPLC (acetonitrile/water) gave amide87 (0.0485 grams, 31% over two steps). 1H NMR (500 MHz, CDCl3) δ 8.22(d, J=8.2 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 7.18(d, J=8.0 Hz, 1H), 6.97 (s, 1H), 5.75 (s, 1H), 4.49 (t, J=5.7 Hz, 2H),3.48 (t, J=4.0 Hz, 2H). LRMS m/z Calcd. for C12H10N4O2: 230.08038,found: 231.08 [M+1].

Example 89 tert-butyl5-(9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-ylcarbamate

Step 1

4-Fluoro-2-hydroxybenzaldehyde (1.918 g, 0.01369 mol), ethanedial (1.884mL, 0.04107 mol), 14.8 M ammonium hydroxide in water (14 mL, 0.21 mol)and methanol (34 mL, 0.84 mol) were combined in a round botton flask andthe reaction mixture stirred overnight at room temperature. Complete byLCMS. Concentrated in vacuo and the crude solid was dissolved in 1 M HCluntil pH was ˜8 with pH paper. Extracted the product with ethyl acetate,washed with brine, dried over magnesium sulfate and concentrated invacuo again. Purified by flash chromatography in the ISCO 0% to 50%ethyl acetate in heptanes and concentrated in vacuo to give5-fluoro-2-(1H-imidazol-2-yl)phenol (0.92 g, 37.7% yield).

Step 2

5-fluoro-2-(1H-imidazole-2-yl)phenol (0.90 g, 5.0 mmol) was dissolved inN,N-Dimethylformamide (40 mL, 500 mmol). Cesium carbonate (6.6 g, 20mmol) was added, followed by 1,2-Dibromoethane (1.7 mL, 20 mmol) andheated at 90° C. with a vigreux condensation column attached for 3hours. Complete by LCMS. Diluted with water and extracted with ethylacetate. Acidified the aqueous layer to pH ˜5 with HCl and extractedwith ethyl acetate. The combined organics were concentrated in vacuo andpurified by flash chromatography on the ISCO 0-50% ethyl acetate inhexanes and concentrated in vacuo to give9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.69 g, 67%yield)

Step 3

9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.69 g, 3.4mmol), N-Iodosuccinimide (2.83 g, 12.6 mmol), and N,N-Dimethylformamidein a round bottom flask and let stir for four days. Diluted with ethylacetate and partitioned with Sat. Sodium bicarbonate and water (50/50).The aqueous layer was extracted once more with ethyl acetate and thecombined organics were dried over magnesium sulfate and concentrated invacuo and purified by flash chromatography on the ISCO 0-40% ethylacetate in hexanes to give9-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(1.25 g, 81% yield)

Step 4

9-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(1.24 g, 2.74 mmol) was dissolved in tetrahydrofuran (25 mL, 310 mmol)and cooled to −78° C. in a dry ice/acetone bath. Added 3.0Methylmagnesium bromide in ether (1.37 mL and allowed the reaction towarm up to −40° C. and stir for 4 hours. Complete by LCMS. Diluted with100 mL of saturated ammonium chloride and extracted with ethyl acetate.Dried over magnesium sulfate, concentrated in vacuo and purified byflash chromatography on the ISCO 0-40% ethyl acetate in hexanes to give9-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.794g, 88% yield)

Step 5

A round bottom flask containing9-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazapine (0.794g, 2.40 mmol) was purged thoroughly with nitrogen. Palladium (II)acetate (27 mg, 0.12 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (139 mg, 0.24 mmol) wasadded sequentially with more purging. Methanol (10 mL, 200 mmol) andtriethylamine (30 mL, 200 mmol) purged with nitrogen were added and thereaction mixture was purged with Carbon monoxide for 5 minutes. TwoCarbon monoxide balloons were attached and the reaction mixture washeated at 50° C. for 4.5 hours. Complete formation of the methyl esterwas confirmed by LCMS. Purged reaction with nitrogen and concentrated invacuo. Purified the ester by flash chromatography on the ISCO 0 to 50%ethyl acetate in heptane and concentrated in vacuo. The ester wasdissolved in tetrahydrofuran and (20 mL, 200 mmol) and 1 M Lithiumhydroxide was added (7.22 mL) and the reaction was stirred for threedays. Complete hydrolysis by LCMS. Adjusted to pH ˜5 with 1 M HCl andextracted off the product with dichloromethane and 5% methanol to give9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylicacid (0.386 g, 64.6% yield)

Step 6

Suspended9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylicacid (0.65 g, 2.6 mmol) in dichloromethane (15 mL, 230 mmol) and added2.0 M oxalyl chloride in dichloromethane (2.0 mL) followed byN,N-Dimethylformamide (81 uL) and since the reaction still was not insolution toluene was added (15 mL, 140 mmol) and the mixture heated witha heat gun until about half was dissolved. Let stir 30 minutes andconcentrated in vacuo to get the acid chloride. This was dissolved in 20mL dichloromethane and the intermediate was added (0.50 g, 2.6 mmol) andtriethylamine (1.1 mL, 7.8 mmol) in dichloromethane (50 mL, 800 mmol).The reaction mixture was stirred for 3 hours and was mostly complete byLCMS. Added water and extracted with dichloromethane 3×. Washed withbrine, dried over magnesium sulfate and concentrated in vacuo andpurified by flash chromatography on the ISCO 0-50% ethyl acetate inheptane to give acylthiourea intermediate (0.20 g, 18% yield).

Step 7

Acylthiourea intermediate (200 mg, 0.4 mmol) was dissolved inN,N-Dimethylformamide (10 mL, 100 mmol) and N,N-Diisopropylamine (0.29mL, 1.662 mmol) was added followed by isopropylhydrazine hydrochloride(68.92 mg, 0.62 mmol). The reaction was stirred at room temperatureovernight. Complete reaction confirmed by LCMS. Diluted with water andextracted with DCM 3 times. The combined organic layers were dried overdried over magnesium sulfate and concentrated in vacuo. The product waspurified by flash chromatography on the ISCO 0 to 10% methanol indichloromethane to give tert-butyl5-(9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-ylcarbamate(200 mg, 100% yield)

Example 9010-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

Step 1: 4-fluoro-2-(1H-imidazol-2-yl)phenol

5-fluoro-2-hydroxybenzaldehyde (5.0 g, 36 mmol), ethanedial (4.912 mL,107 mmol), 14.8 M ammonium hydroxide in water (40 mL, 600 mmol), andmethanol (90 mL, 2000 mmol) were combined in a round bottom flask andlet stir at room temperature overnight. Complete reaction was confirmedby LCMS. Concentrated in vacuo and added 1 M HCL until pH was ˜8.Extracted with ethyl acetate, washed with brine, dried over magnesiumsulfate and concentrated in vacuo. Purified by flash chromatography 0 to50% ethyl acetate in heptane to give 4-fluoro-2-(1H-imidazol-2-yl)phenol(2.24 g, 35% yield)

Step 2

Following the procedures of Example 89,4-fluoro-2-(1H-imidazol-2-yl)phenol was converted to10-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide.

Example 912-Bromo-1-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-ethanone

Step 1

Acetic acid hydrazide (100 g, 1.35 mol) was suspended in acetone (991mL, 13.5 mol) and cyclohexane (1.5 L). The reaction mixture was heatedat 55° C. for 16 h, during which the solids dissolved to give acolourless solution. The reaction mixture was concentrated in vacuo togive Acetic acid isopropylidenehydrazide as a white solid (153 g, 100%).1H NMR 400 MHz (CDCl3) δ: 8.25 (1H, br s), 2.26 (3H, s), 2.00 (3H, s),1.83 (3H, s)

Step 2

To a solution of acetic acid isopropylidenehydrazide (153 g, 1.35 mol)in IMS (1.5 L) was added platinum oxide (0.66 g) and the reactionmixture stirred under an atmosphere of hydrogen at RT until 1H NMRshowed complete consumption of acetic acid isopropylidenehydrazide (˜48h). The reaction mixture was filtered through a plug of Celite® and thefiltrate concentrated in vacuo to give Acetic acid N′-isopropylhydrazideas a colourless oil which crystallised on standing (154.6 g). 1H NMR 400MHz (CDCl3) δ: 3.12 (1H, sept, J=6.3 Hz), 1.96 (3H, s), 1.04 (6H, d,J=6.3 Hz)

Step 3

To a solution of ethyl thiooxamate (29.6 g, 0.22 mol) in DCM (260 mL) atRT was added trimethyloxonium tetrafluoroborate (34.5 g, 0.23 mol) andthe mixture stirred at RT for 2 h. During this time the yellow colourfaded and a thick white precipitate was formed. Acetic acidN′-isopropylhydrazide (27.1 g, 0.23 mol) and TEA (30.9 mL, 0.22 mol)were added as a solution in DCM (75 mL) causing the precipitate todissolve. The reaction mixture was stirred at reflux for 5 h then at RTfor 10 h. The reaction mixture was washed with water, and the aqueouslayer extracted with DCM (2×50 mL). The combined organic extracts werewashed with brine, dried (MgSO4) and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient0-100% ethyl acetate in cyclohexane) to give2-Isopropyl-5-methyl-2H-[1,2,4]triazole-3-carboxylic acid ethyl ester asa pale yellow oil which crystallised on standing (15.6 g, 32%). 1H NMR400 MHz (CDCl3) δ: 5.49 (1H, sept, J=6.7 Hz), 4.45 (2H, t, J=7.2 Hz),2.43 (3H, s), 1.50 (6H, d, J=6.7 Hz), 1.44 (3H, t, J=7.2 Hz)

Step 4

To a solution of 2-isopropyl-5-methyl-2H-[1,2,4]triazole-3-carboxylicacid ethyl ester (12.09 g, 61.3 mmol) and dibromomethane (8.63 mL, 122.6mmol) in THF (500 mL) at −78° C. was added methyllithium (40.9 mL, 122.6mmol, 3M solution in diethoxymethane) dropwise. The reaction mixture wasstirred at −78° C. for 15 min. Acetic acid (3 mL) was added and thereaction mixture allowed to warm to RT. The reaction mixture was dilutedwith water and extracted with ethyl acetate (3×30 mL). The combinedorganic extracts were washed with brine, dried (MgSO4) and concentratedin vacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 0-100% ethyl acetate in cyclohexane) to give2-Bromo-1-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-ethanone as acolourless oil which crystallised on standing (11.26 g, 75%). 1H NMR 400MHz (CDCl3) δ: 5.41 (1H, sept, J=6.6 Hz), 4.67 (2H, s), 2.44 (3H, s),1.49 (6H, d, J=6.6 Hz)

Example 922-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol

Step 1: 4-Chloro-5-iodo-pyridin-2-ylamine

To a solution of 2-amino-4-chloropyridine (150 g, 0.78 mol) in DMF (1.5L) was added NIS (341 g, 1.52 mol) and the reaction mixture stirred atRT for 18 h before being concentrated in vacuo to 300 mL volume. Theresultant residue was poured into 10% aqueous sodium thiosulfatesolution (1.2 L), stirred for 15 min and the precipitate formedcollected by filtration, washed with water then dried at 35° C. in vacuoto give the title compound as a pale brown solid (185 g, 62%). 1H NMR400 MHz (CDCl3) δ: 8.33 (1 H, s), 6.68 (1 H, s), 4.52 (2 H, s).

Step 2: 4-Chloro-5-iodo-2-methoxy-pyridine

To a solution of 4-chloro-5-iodo-pyridin-2-ylamine (64.2 g, 0.25 mol) inmethanol (1.1 L) and TFA (93.7 mL, 1.26 mol) was added tert-butylnitrite (150 mL, 1.26 mol) so as to maintain temperature less than 3° C.The resultant mixture was stirred at RT for 1 h then allowed to warm toRT and stirred for 16 h. The reaction was quenched by the carefuladdition of water then concentrated in vacuo to ¼ volume. The resultantresidue was treated with water (1 L) and the precipitate formedcollected by filtration and dried in vacuo at 35° C. to give the titlecompound (62.3 g, 92%). Contains 16% impurity. ¹H NMR 400 MHz (DMSO-d)δ: 8.56 (1 H, s), 7.20 (1 H, s), 3.86 (3 H, s).

Step 3: 4-Chloro-6-methoxy-nicotinonitrile

A suspension of 4-chloro-5-iodo-2-methoxy-pyridine (30.5 g, 0.11 mol),zinc (II) cyanide (7.97 g, 68 mmol), Pd(PPh3)4 (6.56 g, 5.66 mmol) andDMF (450 mL) was degassed and then heated at 120° C. for 1 h beforebeing concentrated in vacuo. The resultant residue was treated withwater then extracted with DCM, the organic extract dried (MgSO4),filtered, then concentrated in vacuo. The resultant residue wascrystallized from DCM to give the title compound (10.1 g, 54%). Themother liquors were concentrated in vacuo and the residue subjected toflash chromatography (SiO2 gradient 0 to 100% ethyl acetate incyclohexane) then crystallization from cyclohexane to give the furthertitle compound (5.16 g, 28%, 82% total). 1H NMR 400 MHz (CDCl3) δ: 8.45(1 H, s), 6.90 (1 H, s), 4.01 (3 H, s).

Step 4: 4-Chloro-6-methoxy-nicotinamidine hydrochloride

To a solution of 4-chloro-6-methoxy-nicotinonitrile (10.1 g, 59.7 mmol)in THF (300 mL) at −78° C. was added LiHMDS (65.7 mL) dropwise and thereaction mixture stirred for 30 min before allowing to warm to RT andstirring for a further 1 h. The reaction was quenched by the addition of1N HCl (to pH ˜1) and then extracted three times with ethyl acetate. Theaqueous layer was concentrated in vacuo to give brown solid which wasazeotroped with toluene to give the title compound as a tan solid.Mixture with ammonium chloride, 72% title compound by weight. (15.2 g,83%). ¹H NMR 400 MHz (DMSO-d) δ: 9.68 (4 H, d, J=15.79 Hz), 8.46 (1 H,s), 7.47 (5 H, t, J=50.66 Hz), 7.27 (1 H, s), 3.95 (3 H, s).

Step 5: 4-Chloro-5-[b4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridine

A suspension of 4-chloro-6-methoxy-nicotinamidine hydrochloride (18.4mmol) and potassium bicarbonate (7.37 g, 73.6 mmol) in THF (42 mL) andwater (8.5 mL) was heated to reflux and treated with a solution of2-bromo-1-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-ethanone (4.53g, 18.4 mmol) in THF (14 mL) added dropwise. The reaction mixture washeated at reflux for 18 h before removal of volatile solvent in vacuo.The resultant suspension was filtered and the residue washed with waterthen dried to give the title compound as a brown solid (5.91 g, 97%).LCMS: RT=2.68 min, [M+H]+=333/335. 1H NMR 400 MHz (CDCl3) δ: 10.41 (1 H,s), 9.02 (1 H, s), 7.81 (1 H, s), 6.87 (1 H, s), 5.91 (1 H, m), 4.00 (3H, s), 2.41 (3 H, s), 1.55 (6 H, d, J=6.71 Hz).

Step 6:2-[2-(4-Chloro-6-methoxy-pyridin-3-yl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol

A suspension of4-chloro-5-[4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridine(5.9 g, 17.7 mmol) in toluene (20 mL) was treated with ethylenecarbonate (50 mL) and heated at 130° C. for 2.5 h. The cooled reactionmixture was concentrated in vacuo then diluted with DCM and passedthrough a pad of silica eluting with DCM then 20% methanol in DCM.Methanolic fractions were combined and concentrated in vacuo and theresultant residue subjected to recrystallisation from acetonitrile togive the title compound as a pale tan solid (2.27 g, 34%). LCMS: RT=2.53min [M+H]+=377/379. 1H NMR 400 MHz (CDCl3) δ: 8.25 (1H, s), 8.05 (1H,s), 6.92 (1H, s), 5.82-5.80 (1H, m), 4.00 (3H, s), 3.97 (2H, t, J=4.92Hz), 3.88 (2H, t, J=4.92 Hz), 2.38 (3H, s), 1.48 (6H, d, J=6.63 Hz).

Step 7:2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-methoxy-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene

A solution of2-[2-(4-chloro-6-methoxy-pyridin-3-yl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol(2.25 g, 5.97 mmol) in DMF (30 mL) was cooled to 0° C. and treated withsodium hydride (239 mg, 5.97 mmol), the reaction mixture stirred at 0°C. for 30 min then allowed to warm to RT and stirred for 2 h. Thereaction mixture was re-cooled to 0° C. and treated with water (400 mL),the precipitated product filtered off and washed with water then driedin vacuo to give the title compound as a white solid (1.02 g, 50%). LCMSRT=2.68 min, [M+H]+=341. ¹H NMR 400 MHz (DMSO-d) δ: 9.15 (1 H, s), 7.87(1 H, s), 6.42 (1 H, s), 5.84 (1 H, m), 4.57-4.56 (4 H, m), 3.89 (3 H,s), 2.25 (3 H, s), 1.46 (6 H, d, J=6.60 Hz).

Step 8

A solution of2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-methoxy-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene(1.0 g, 2.97 mmol) in 48% aqueous HBr (5 mL) and acetic acid (5 mL) washeated at 80° C. for 7.5 h before being concentrated in vacuo. Theresultant residue was suspended in water (10 mL) and pH adjusted to ˜6using 5N aqueous NaOH. The precipitate formed was filtered off, washedwith water then dried in vacuo to give2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olas a white solid (1.01 g, 100%). LCMS RT=2.01 min, [M+H]+=327. ¹H NMR400 MHz (DMSO-d) δ: 8.42 (1 H, s), 7.85 (1 H, s), 5.85 (1 H, s),5.69-5.65 (1 H, m), 4.55-4.54 (2 H, m), 4.50-4.46 (2 H, m), 2.27 (3 H,s), 1.44 (6 H, d, J=6.59 Hz).

Example 932-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol

Step 1: 4-Chloro-5-[b4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridine

A suspension of 4-chloro-6-methoxy-nicotinamidine hydrochloride (50.9mmol) and potassium bicarbonate (20.4 g, 202.5 mmol) in THF (128 mL) andwater (21 mL) was heated to reflux and treated with a solution of2-chloro-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (9.55 g, 50.9mmol) in THF (25 mL) added dropwise. The reaction mixture was heated atreflux for 24 h before removal of volatile solvent in vacuo. Theresultant residue was diluted with water and extracted with ethylacetate. The combined extracts were dried (Na2SO4), treated withcharcoal (15 g), filtered and concentrated in vacuo to give a solid. Thesolid was triturated with 10% diethyl ether in pentane then dried at 50°C. in vacuo to give 4-Chloro-5-[b4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridineas a pale brown solid (8.74 g, 54%). LCMS RT=2.86 min, [M+H]+=319/321.¹H NMR 400 MHz (CDCl3) δ: 9.03 (1 H, s), 7.89 (1 H, s), 7.83 (1 H, s),7.26 (1 H, s) 6.88 (1 H, s), 4.01 (3 H, s), 1.58 (6 H, d, J=6.63 Hz).

Step 2:2-[2-(4-Chloro-6-methoxy-pyridin-3-yl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol

To warmed ethylene carbonate (34 g) was added4-chloro-5-[4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridine(8.74 g, 27.4 mmol) and the mixture heated at 130° C. for 3 h. Thecooled reaction mixture was diluted with DCM and loaded onto silica (150g). The silica was washed with DCM then 5% methanol in DCM. Methanolicfractions were combined and concentrated in vacuo to give the titlecompound as a brown foam (7.52 g, 75%). LCMS RT=2.65, [M+H]+=363/365. 1HNMR 400 MHz (CDCl3) δ: 8.27 (1 H, s), 8.02 (1 H, s), 7.85 (1 H, s), 6.93(1 H, s), 5.98-5.82 (1 H, m), 4.00 (5 H, m), 3.88 (2 H, t, J=5.11 Hz),1.51 (6 H, d, J=6.62 Hz).

Step 3:2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-methoxy-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene

A solution of2-[2-(4-chloro-6-methoxy-pyridin-3-yl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol(7.52 g, 20.7 mmol) in DMF (100 mL) was cooled to 0° C. and treated withsodium hydride (804 mg, 20.1 mmol), the reaction mixture stirred at 0°C. for 10 min then allowed to warm to RT and stirred for 72 h. Furthersodium hydride (150 mg) was added and stirring continued until nostarting material remained before removal of solvent in vacuo. Theresidue was dissolved in ethyl acetate and the resultant solution washedthree times with saturated brine then dried (Na2SO4), filtered andconcentrated in vacuo. The resultant residue was triturated inpentane/diethyl ether (5:1) to give the title compound as a brown solid(5.38 g, 79%). LCMS RT=2.86, [M+H]+=327. 1H NMR 400 MHz (CDCl3) δ: 9.35(1 H, s), 7.87 (1 H, s), 7.63 (1 H, s), 6.37 (1 H, s), 6.03-6.02 (1 H,m), 4.54-4.53 (2 H, m), 4.53-4.33 (2 H, m), 3.99 (3 H, s), 1.57 (6 H, d,J=6.63 Hz).

Step 4

A solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-methoxy-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene(1.0 g, 2.97 mmol) in acetic acid (40 mL) was treated with 48% aqueousHBr (37.7 mL) and heated at 80° C. for 5 h before being concentrated invacuo. The resultant residue was suspended in water (60 mL) and pHadjusted to ˜6 using 5N aqueous NaOH. The precipitate formed wasfiltered off, washed with water then dried in vacuo. The resultant solidwas triturated in acetone to give2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olas a beige solid (3.58 g, 69%). LCMS RT=2.04 min, [M+H]+=313. ¹H NMR 400MHz (DMSO-d) δ: 8.42 (1 H, s), 7.90 (1 H, s), 7.83 (1 H, s), 5.84 (1 H,s), 5.78 (1 H, m), 4.71-4.30 (4 H, m), 1.45 (6 H, d, J=6.60 Hz).

Example 942-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulenehydrochloride

Step 1 Trifluoro-methanesulfonic acid2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester

A suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol(238 mg, 0.76 mmol) in DMF (2.2 mL) was treated with sodium hydride (65%dispersion in mineral oil, 34 mg, 0.91 mmol), the reaction mixtureheated at 40° C. for 1.5 h then cooled to RT.Benzenebis(trifluoromethane) sulfonamide (327 mg, 0.91 mmol) was addedand the reaction mixture stirred at RT for 24 h before being dilutedwith ethyl acetate (60 mL) and washed with brine (4×20 mL). Theresultant solution was dried (MgSO4), filtered and concentrated in vacuoto give a solid which was triturated in diethyl ether to giveTrifluoro-methanesulfonic acid2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester as a white solid (44 mg). The mother liquors from trituration wereconcentrated in vacuo, the resultant residue recrystallised frommethanol to give further compound (39 mg, 25% total). LCMS RT=3.27 min,[M+H]+=445. ¹H NMR 400 MHz (DMSO-d6) δ: 9.32 (1 H, s), 8.04 (1 H, s),7.93 (1 H, s), 7.36 (1 H, s), 5.89 (1 H, m), 4.74 (2 H, m), 4.63 (2 H,m), 1.48 (6 H, d, J=6.58 Hz)

Step 2

To a mixture of trifluoro-methanesulfonic acid2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester (83 mg, 0.19 mmol) and 2N aqueous sodium carbonate (600 L) in DMF(1.2 mL) was added palladium bis(dibenzylideneacetone) (6 mg, 0.01mmol), triphenylphosphine (4 mg, 0.015 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (75 mg, 0.24 mmol). The reaction mixture wasdegassed and then heated at 90° C. under an atmosphere of argon for 2 hbefore being concentrated in vacuo. The resultant residue waspartitioned between ethyl acetate and water, the aqueous extracted withethyl acetate (×3) and the combined organic extracts dried (MgSO4),filtered and concentrated in vacuo. The resultant residue was subjectedto flash chromatography (SiO2, gradient 0 to 10% methanol in ethylacetate) to give4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester as a white solid (41 mg, 45%). LCMS (*) RT=3.24min, [M+H]+=478. 1H NMR 400 MHz (CDCl3) δ: 9.65 (1 H, s), 7.94 (1 H, s),7.89 (1 H, s), 7.00 (1 H, s), 6.84 (1 H, s), 4.60 (2 H, s), 4.50 (2 H,s), 4.18 (2 H, s), 3.67 (2 H, s), 2.62 (2 H, s), 1.59 (6 H, d, J=6.62Hz), 1.50 (9 H, s)

Step 3

A mixture of4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (89 mg, 0.19 mmol) in IMS (10 mL) was treated withplatinum oxide (10 mg), the reaction mixture degassed and stirred at RTunder an atmosphere of hydrogen for 72 h. Further platinum oxide (10 mg)was added and stirring continued at RT for 18 h before the filteringthrough Celite® and concentrating in vacuo. The resultant residue wassubjected to flash chromatography (SiO2, gradient 0 to 5% methanol inDCM) to give4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (58 g, 64%). LCMS RT=2.72, [M+H]+=480

Step 4

A solution of4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (58 mg, 0.12 mmol) in DCM (0.5 mL) and methanol(0.3 mL) was treated with 4M HCl in dioxane (0.8 mL) and the reactionmixture stirred at RT for 1.5 h before being concentrated in vacuo. Theresultant residue was triturated with diethyl ether to give2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulenehydrochloride (66 mg, 100%). LCMS RT=1.68 min, [M+H]+=380

Example 1022-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide102

Oxalyl chloride in methylene chloride (2.00 M, 3.0 mL) was added to asuspension of2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid (112 mg, 0.178 mmol) in 30 ml of methylene chloride. Catalyticamount of N,N-Dimethylformamide (1.0 uL, 0.013 mmol) was added and themixture was stirred for 2 hours. The mixture was filtered, the filtratewas concentrated in vacuum and the residue dried in high vacuum for 1hour. The above residue was dissolved in N,N-dimethylacetamide (3.0 mL,32 mmol) and saturated with gaseous ammonia. The mixture was stirred for20 min, concentrated in vacuum, dissolved in aqueous methanol andsubjected to RP HPLC purification to yield 18.5 mg of 102 (26%), MS:407.1. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=2.2, 1H), 8.20 (s, 1H), 7.80(s, 1H), 7.72-7.51 (m, 6H), 7.29 (s, 1H), 7.00 (d, J=8.5, 1H).

Example 1032-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-8-bromo-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole103

A solution of 2,4-difluorophenyl hydrazine (20 g, 0.14 mol) in formamide(60 mL) was heated at 120° C. for 18 h. The cooled reaction mixture wasdiluted with saturated aqueous sodium hydrogen carbonate and ethylacetate forming an emulsion. The emulsion was filtered through Celite®,the aqueous extracted with ethyl acetate. The combined organic extractswere dried (Na2SO4), filtered and concentrated in vacuo and theresultant solid subjected to flash chromatography (SiO2, gradient 0 to100% ethyl acetate in cyclohexane) to give1-(2,4-Difluoro-phenyl)-1H-[1,2,4]triazole as a white solid (15.7 g,62%). ¹H NMR δ (ppm)(CDCl3): 8.60 (1 H, d, J=2.83 Hz), 8.12 (1 H, s),7.91-7.83 (1 H, m), 7.10-7.04 (2 H, m).

Under an atmosphere of nitrogen a solution of1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (15.7 g, 86.7 mmol) in THF(300 mL) at −78° C. was treated with n-butyllithium (38 mL, 2.5 M, 95.3mmol) dropwise. After stirring for 1.5 h a solution of hexachloroethane(22.6 g, 95.3 mmol) in THF (30 mL) was added dropwise. The resultantreaction mixture was stirred for 1.5 h before allowing to warm to RT andquenching with water. The resultant mixture was diluted with water andextracted with ethyl acetate, the combined organic extracts were dried(Na2SO4), filtered and concentrated in vacuo to give an oil whichcrystallised on standing. The solid was recrystallised from cyclohexaneto give 5-Chloro-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (12.4 g,66%). ¹H NMR δ (ppm)(CDCl3): 8.04 (1 H, s), 7.51-7.43 (1 H, m),7.10-7.04 (2 H, m).

To a solution of 8-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(2.12 g, 7.99 mmol) and5-chloro-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (2.58 g, 12.0 mmol)in THF (10 mL) was added cesium carbonate (3.9 g, 12.0 mmol) and thereaction mixture heated at 180° C. for 60 min using microwaveirradition. The cooled reaction mixture was diluted with water andextracted with ethyl acetate, the combined organic extracts were washedwith brine, then dried (MgSO4), filtered and concentrated in vacuo. Theresultant residue was triturated in hot cyclohexane to give 103 (1.62 g,46%). ¹H NMR (DMSO-d6, 400 MHz): δ 8.45 (s, 1 H); 8.30 (s, 1 H);7.84-7.77 (m, 1 H); 7.66-7.58 (m, 1 H); 7.37-7.30 (m, 1 H); 7.27 (d,J=8.6 Hz, 1 H); 7.22 (d, J=2.0 Hz, 1 H); 7.13 (dd, J=8.6, 2.1 Hz, 1 H);4.26 (t, J=5.0 Hz, 2 H); 3.06 (t, J=5.0 Hz, 2 H)

Example 1042-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide104

Following the procedure for 243,2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid, ammonium chloride, HATU, diisopropylethylamine and DMF werereacted to give 104. Yield 51%. MS: 407.0. 1H NMR (400 MHz, DMSO) δ 8.21(s, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.74 (d, J=7.0, 1H), 7.69-7.54 (m,4H), 7.47 (s, 1H), 7.44-7.36 (m, 2H), 4.48 (d, J=7.6, 4H)

Example 1052-(1-isopropyl-1H-1,2,4-triazol-5-yl)-8-(pyrazol-4-yl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole105

8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(53 mg, 0.14 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (36 mg,0.18 mmol), tris(dibenzylidineacetone)di-palladium (0) (2.2 mg, 1.7 mol%), 2,4′,6′-diisopropyl-1,1′-biphenyl-2-yldicyclohexylphosphine (5.3 mg,9 mol %) and K3PO4 (89 mg, 0.42 mmol) were combined in a reaction vial,the atmosphere evacuated and back-filled with nitrogen. Dioxane (1 mL)and water (0.1 mL) were added and the reaction mixture heated at refluxfor 18 h. Further4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (36 mg,0.18 mmol), tris(dibenzylidineacetone)di-palladium (0) (2.2 mg, 1.7 mol%), and 2,4′,6′-diisopropyl-1,1′-biphenyl-2-yldicyclohexylphosphine (5.3mg, 9 mol %) were added and heating continued for a further 18 h. Thereaction mixture was diluted with ethyl acetate, decanted and thenconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 10 to 60% ethyl acetate in cyclohexane)to give 105 as a white solid (12 mg, 24%). ¹H NMR (CDCl3, 400 MHz): δ8.28 (d, J=8.2 Hz, 1 H); 8.08 (s, 1 H); 7.90 (s, 2 H); 7.80 (s, 1 H);7.30 (dd, J=8.2, 1.8 Hz, 1 H); 7.23 (d, J=1.8 Hz, 1 H); 5.73-5.59 (m, 1H); 4.42-4.35 (m, 2 H); 3.20-3.13 (m, 2 H); 1.62 (d, J=6.6 Hz, 6 H). 1Exchangeable proton not observed. LCMS: RT=9.48 min, M+H+=362

Example 1062-(1-isopropyl-1H-1,2,4-triazol-5-yl)-8-bromo-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole106 Step 1: 1-Isopropyl-1H-[1,2,4]triazole

A solution of isopropyl hydrazine hydrochloride (60 g, 0.54 mmol) informamide (270 mL) was heated at 130° C. for 3 days. The cooled solutionwas diluted with saturated brine (700 mL) and extracted with ethylacetate (4×1 L). The combined organics were dried (Na2SO4), filtered andconcentrated in vacuo to give an oil. The oil was subjected todistillation under reduced pressure (25 mbar by 85-90° C.) to give1-Isopropyl-1H-[1,2,4]triazole as a colourless oil (54 g, 90%). ¹H NMR δ(ppm)(CDCl3): 8.10 (1 H, s), 7.95 (1 H, s), 4.63-4.50 (1 H, m), 1.56 (6H, d, J=6.69 Hz).

Step 2: 5-Chloro-1-isopropyl-1H-[1,2,4]triazole

Under an atmosphere of nitrogen a solution of1-isopropyl-1H-[1,2,4]triazole (19 mmol) in THF (50 mL) at −78° C. wastreated with n-butyllithium (11.4 mL, 2.5 M, 28.5 mmol) dropwise givinga cream yellow suspension. Further n-butyllithium (3.8 mL, 2.5 M, 9.5mmol) was added after 1 h and stirring continued for a further 1.5 h.1,1,2-trichlorotrifluoroethane (4.57 mL, 38 mmol) was added dropwisegiving a dark brown solution. The resultant reaction mixture was stirredfor 15 min before being quenched by the addition of saturated aqueousNaHCO3 (20 mL) then allowed to warm to RT. The resultant mixture wasextracted twice with diethyl ether, the combined organic extracts dried(Na2SO4), filtered and concentrated in vacuo to give5-Chloro-1-isopropyl-1H-[1,2,4]triazole as a dark oil (3.9 g) which wasused in the subsequent step without further purification. ¹H NMR δ(ppm)(CDCl3): 7.85 (1 H, s), 4.73-4.63 (1 H, m), 1.54-1.46 (6 H, m).

An ice-cooled suspension of sodium hydride (60% dispersion 1.09 g, 38mmol) was treated portionwise with8-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (3.6 g, 13.6mmol) giving a deep red suspension.5-Chloro-1-isopropyl-1H-[1,2,4]triazole (19 mmol) was added and themixture heated at 80° C. under nitrogen for 72 h. The cooled reactionmixture was quenched with water and extracted twice with ethyl acetate.The combined organic extracts were dried (Na2SO4), filtered and thenconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0 to 15% ethyl acetate in cyclohexane).Appropriate fractions were combined and recrystallised from methanol andcyclohexane/ethyl acetate to give 106 as a tan solid (789 mg, 16%). ¹HNMR (CDCl3, 400 MHz): δ 8.15-8.11 (m, 1 H); 8.08 (s, 1 H); 7.80 (s, 1H); 7.28-7.23 (m, 2 H); 5.65-5.53 (m, 1 H); 4.38-4.31 (m, 2 H);3.18-3.10 (m, 2 H); 1.60 (d, J=6.6 Hz, 6 H).

Example 1072-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole-8-carboxamide107

To a suspension of8-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(80 mg, 0.18 mmol), hydroxylamine hydrochloride (25 mg, 0.36 mmol),molybdenum hexacarbonyl (24 mg, 0.09 mmol), tri-tert-butylphosphinetetrafluoroborate (5 mg, 10 mol %),trans-di-g-acetatobis[2-(di-o-tolylphosphino)benzyl]dipalladium(II) (8.4mg, 5 mol %) in dioxane (4 mL) were added1,8-diazabicyclo[5.4.0]undec-7-ene (27 μL, 0.18 mmol) and DIPEA (62 μL,0.36 mmol). The reaction mixture was heated at 150° C. under microwaveirradiation for 30 mins, and diluted with ethyl acetate. The organiclayer was washed with water, saturated aqueous sodium bicarbonatesolution followed by brine, dried (Na2SO4) and concentrated in vacuo.The resultant residue was subjected flash chromatography (SiO2, 20 to90% ethyl acetate in cyclohexane) to give an solid, which wasrecrystallised from methanol to give 107 as a white solid (17 mg, 23%).¹H NMR (DMSO-d6, 400 MHz) δ 8.48 (s, 1 H); 8.31 (s, 1 H); 7.98 (s, 1 H);7.87-7.79 (m, 1 H); 7.69-7.61 (m, 1 H); 7.49 (d, J=1.7 Hz, 1 H); 7.43(dd, J=8.3, 1.8 Hz, 1 H); 7.40-7.32 (m, 3 H); 4.27 (t, J=5.0 Hz, 2 H);3.09 (t, J=5.0 Hz, 2 H). LCMS: RT=8.72 min, M+H+=409

Example 1082-(4-isopropyl-4H-1,2,4-triazol-5-yl)-9-(pyrazol-4yl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole108

A suspension of9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(78 mg, 0.21 mmol),4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (61 mg, 0.31mmol), tetrakis(triphenylphosphine) palladium (0) (24 mg, 0.021 mmol)and sodium carbonate (45 mg, 0.42 mmol) in acetonitrile (6 mL) and water(3 mL) under nitrogen was heated at 140° C. for 25 min using microwaveirradiation. The reaction mixture was diluted with ethyl acetate andwater, the organic layer was isolated and washed with brine, dried(Na2SO4), concentrated in vacuo. The resultant residue was subjected toflash chromatography (SiO2, gradient 0 to 50% ethyl acetate incyclohexane) followed by recrystallisation from acetonitrile andtrituration in pentane to afford 108 as an off-white solid (16 mg, 20%).(67261) ¹H NMR (DMSO-d6, 400 MHz): δ 12.91 (s, 1 H); 8.38 (d, J=2.3 Hz,1 H); 8.32 (s, 1 H); 8.03 (s, 1 H); 7.97 (s, 2 H); 7.52 (dd, J=8.4, 2.3Hz, 1 H); 7.05 (d, J=8.4 Hz, 1 H); 5.41-5.26 (m, 1 H); 4.35-4.26 (m, 2H); 3.17-3.08 (m, 2 H); 1.55 (d, J=6.6 Hz, 6 H). LCMS: RT=9.38 min,M+H+=362

Example 1092-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide109

To a solution of2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid (0.170 g, 0.000501 mol) dissolved in N,N-Dimethylformamide (7.84mL, 0.101 mol) and treated sequentially with N,N-Diisopropylethylamine(0.524 mL, 0.00300 mol) Ammonium chloride (0.107 g, 0.00200 mol) thenN,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate (0.228 g, 0.000601 mol). The reaction was stirred atr.t. overnight. The reaction was quenched with sat. sodium bicarbonatethen extract with ethyl acetate (3×). The organic layers was dried(Na2SO4) and concentrated in vacuo to give 109 purified on reverse HPLC.MS: (ESI+)=339.1. 1H NMR (400 MHz, DMSO) δ 8.93 (d, J=2.2 Hz, 1H), 7.95(s, 2H), 7.92 (s, 1H), 7.79 (dd, J=8.5, 2.2 Hz, 1H), 7.10 (d, J=8.5 Hz,1H), 5.82 (dt, J=13.2, 6.6 Hz, 1H), 4.56 (s, 4H), 1.49 (d, J=6.6 Hz, 6H)

Example 1102-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-N-methyl-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole-9-carboxamide110

Following Example 107,9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenewas reacted with N,O-dimethylhydroxylamine hydrochloride molybdenumhexacarbonyl, tri-tert-butylphosphine tetrafluoroborate,trans-di-μ-acetatobis[2-(di-o-tolylphosphino)benzyl]dipalladium(II) indioxane. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and DIPEA were added.The reaction mixture was heated at 150° C. under microwave irradiationfor 30 mins, then diluted with ethyl acetate. The organic layer waswashed with water, saturated aqueous sodium bicarbonate solutionfollowed by brine, dried (Na2SO4) and concentrated in vacuo. Theresultant residue was subjected flash chromatographyto give 110 as awhite solid (29 mg, 31%). ¹H NMR (DMSO-d6, 400 MHz): δ 8.75 (d, J=2.3Hz, 1 H); 8.44-8.38 (m, 1 H); 8.33 (s, 1 H); 8.05 (d, J=0.6 Hz, 1 H);7.73 (dd, J=8.5, 2.3 Hz, 1 H); 7.10 (d, J=8.5 Hz, 1 H); 5.31-5.21 (m, 1H); 4.35 (t, J=5.0 Hz, 2 H); 3.13 (t, J=5.0 Hz, 2 H); 2.78 (d, J=4.5 Hz,3 H); 1.51 (d, J=6.6 Hz, 6 H). LCMS: RT=8.24 min, M+H+=353

Example 1112-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-N-(2-hydroxyethyl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole-9-carboxamide111

Following the procedure for 107,9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenewas reacted with ethanolamine to give 111 as a white solid (23 mg, 22%).¹H NMR (400 MHz, DMSO-d6): δ 8.71 (d, J=2.29 Hz, 1 H); 8.35 (t, J=5.57Hz, 1 H); 8.29 (s, 1 H); 8.00 (d, J=0.60 Hz, 1 H); 7.71 (dd, J=8.51,2.33 Hz, 1 H); 7.06 (d, J=8.49 Hz, 1 H); 5.29-5.21 (m, 1 H); 4.65 (t,J=5.60 Hz, 1 H); 4.30 (t, J=4.98 Hz, 2 H); 3.47 (q, J=5.99 Hz, 2 H);3.28 (t, J=4.93 Hz, 2 H); 3.09 (t, J=4.98 Hz, 2 H); 1.46 (d, J=6.59 Hz,6 H). LCMS RT=7.41 min, M+H+=383

Example 112(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)(S-dioxothiomorpholino)methanone112

Following the procedure for 116,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid was reacted with thiomorpholine dioxide to give 112. ¹H NMR(DMSO-d6, 400 MHz): δ 8.06 (d, J=2.1 Hz, 1 H); 8.04 (d, J=0.6 Hz, 1 H);7.50 (dd, J=8.3, 2.1 Hz, 1 H); 7.34 (d, J=8.3 Hz, 1 H); 6.92 (s, 1 H);5.67-5.54 (m, 1 H); 4.57 (t, J=5.9 Hz, 2 H); 3.35-3.26 (br m, 8H); 3.24(t, J=6.0 Hz, 2 H); 1.48 (d, J=6.6 Hz, 6 H). LCMS: RT=8.24 min, M+H+=457

Example 1134-(2-hydroxypropan-2-yl)piperidin-1-yl)(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone113

Following the procedure for 109,2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 2-(piperidin-4-yl)propan-2-ol gave 113. MS: (ESI+)=465.2. 1HNMR (400 MHz, DMSO) δ 8.40 (d, J=1.6 Hz, 1H), 7.96 (s, 1H), 7.92 (s,1H), 7.35 (dd, J=8.4, 1.9 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 5.87-5.69 (m,1H), 4.56 (s, 4H), 4.15 (s, 1H), 1.75 (s, 2H), 1.48 (d, J=6.6 Hz, 7H),1.19 (dd, J=23.3, 11.1 Hz, 2H), 1.05 (s, 7H)

Example 1149-(1-Isopropyl-1H-pyrazol-5-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxamide114

A mixture of 17 mg (0.05 mmol) of9-(1-isopropyl-1H-pyrazol-5-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylicacid, 30 mg, (0.061 mmol) of HATU and 0.022 ml (0.155 mmol) oftriethylamine in 2 ml of DMF was stirred for 10 min. Ammonia (gas) wasbubbled through the mixture for 5 min. The mixture was stirred for 1hour, concentrated in vacuum and partitioned between ethyl acetate and0.01 N aqueous HCl. The organic layer was concentrated and the residuepurified on 4 g silica column eluting with 7-8% Methanol in DCM to give114. Yield 2.4 mg. MS(ESI+) 339.2. 1H NMR (400 MHz, CH3OH+D2O) δ 8.70(d, J=1.8, 1H), 8.33 (s, 1H), 8.05 (d, J=1.8, 1H), 7.52 (s, 1H), 6.48(d, J=1.6, 1H), 5.16 (dd, J=13.2, 6.6, 1H), 4.56 (t, J=5.1, 2H),3.52-3.45 (m, 2H), 1.49 (d, J=6.6, 6H).

Example 1152-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide115

Following the procedure in Example 51,2-(1-Isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid was coupled with ammonia to give 115. MS(ESI+): 338.1. 1H NMR (400MHz, DMSO) δ 8.94 (d, J=2.2, 1H), 7.94 (s, 1H), 7.77 (dd, J=8.5, 2.2,1H), 7.69 (s, 1H), 7.44 (d, J=1.4, 1H), 7.25 (s, 1H), 7.08 (d, J=8.5,1H), 6.40 (d, J=1.7, 1H), 5.34 (dt, J=13.0, 6.4, 1H), 4.52 (dd, J=11.0,5.6, 4H), 1.44 (d, J=6.6, 6H).

Example 116N-(2-hydroxy-2-methylpropyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-9-carboxamide116

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid (0.2 g, 0.59 mmol) was suspended in DMF (5 mL) and DIPEA (0.21 mL,1.2 mmol) added. The resultant solution was treated with HATU (0.23 g,0.6 mmol) and HOBT (81 mg, 0.6 mmol) before the addition of1-amino-2-methyl-propan-2-ol (52.5 mg, 0.59 mmol) then stirred for 18 hat RT. The reaction mixture was concentrated in vacuo and the resultantresidue partitioned between DCM and water. The aqueous layer wasextracted three times with DCM and the combined organic extracts washedwith water, dried (Na2SO4), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient0 to 10% MeOH in ethyl acetate) and recrystallistion from ethyl acetateto give 116 (163 mg, 67%). ¹H NMR (CDCl3, 400 MHz): δ 8.46 (d, J=2.2 Hz,1 H); 7.94 (s, 1 H); 7.72 (dd, J=8.4, 2.2 Hz, 1 H); 7.22 (d, J=8.4 Hz, 1H); 6.86 (s, 1 H); 6.66 (s, 1 H); 5.74-5.61 (m, 1 H); 4.57 (t, J=5.7 Hz,2 H); 3.50 (d, J=5.9 Hz, 2 H); 3.22 (t, J=5.7 Hz, 2 H); 2.18 (s, 1 H);1.59 (d, J=6.6 Hz, 6 H); 1.31 (s, 6 H). LCMS: RT=9.53 min, M+H+=411

Example 117(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)(S-dioxothiomorpholino)methanone117

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid was reacted with thiomorpholine dioxide to give 117. ¹H NMR(DMSO-d6, 400 MHz): δ 8.06 (d, J=2.1 Hz, 1 H); 8.04 (d, J=0.6 Hz, 1 H);7.50 (dd, J=8.3, 2.1 Hz, 1 H); 7.34 (d, J=8.3 Hz, 1 H); 6.92 (s, 1 H);5.67-5.54 (m, 1 H); 4.57 (t, J=5.9 Hz, 2 H); 3.35-3.26 (br m, 8H); 3.24(t, J=6.0 Hz, 2 H); 1.48 (d, J=6.6 Hz, 6 H). LCMS: RT=8.24 min, M+H+=457

Example 118(4-hydroxypiperidin-1-yl)(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)methanone118

Following the procedure for 116,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid was reacted with 4-hydroxy piperidine to give 118 as a white solid.¹H NMR (CDCl3, 400 MHz): δ 8.02 (d, J=2.1 Hz, 1 H); 7.94 (s, 1 H); 7.35(dd, J=8.3, 2.1 Hz, 1 H); 7.23 (d, J=8.3 Hz, 1 H); 6.88 (s, 1 H);5.76-5.62 (m, 1 H); 4.58 (t, J=5.8 Hz, 2 H); 4.19 (br s, 1 H); 4.07-3.98(m, 1 H); 3.82 (br s, 1 H); 3.37 (br s, 2 H); 3.20 (t, J=5.8 Hz, 2 H);1.95 (br s, 2 H); 1.70 (d, J=3.9 Hz, 1 H); 1.67-1.54 (d, J=6.6 Hz, 8 H).LCMS: RT=8.77 min, M+H+=423

Example 119N-(2-(methylsulfonyl)ethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide119

Following the procedure for 109,2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 2-(methylsulfonyl)ethanamine gave 119. MS: (ESI+)=485.1. 1H NMR(400 MHz, DMSO) δ 8.93 (d, J=2.1 Hz, 1H), 8.72 (t, J=5.4 Hz, 1H), 8.10(s, 2H), 7.78 (dd, J=8.6, 2.2 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 5.94 (q,J=8.9 Hz, 2H), 4.58 (s, 4H), 3.69 (dd, J=12.7, 6.5 Hz, 2H), 3.38 (t,J=6.8 Hz, 2H), 3.04 (s, 3H)

Example 120(4-isopropylpiperazin-1-yl)(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone120

Following the procedure for 109,2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 1-isopropylpiperazine gave 120. MS: (ESI+)=490.2. 1H NMR (400MHz, DMSO) δ 8.38 (d, J=2.0 Hz, 1H), 8.10 (d, J=5.4 Hz, 2H), 7.37 (dd,J=8.4, 2.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 5.87 (q, J=8.8 Hz, 2H), 4.57(s, 4H), 3.49 (s, 4H), 2.68 (dt, J=13.0, 6.6 Hz, 1H), 2.45 (s, 4H), 0.97(d, J=6.5 Hz, 6H)

Example 121N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide

Following the procedure for 109,2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 2-amino-2-methylpropan-1-ol gave 121. MS: (ESI+)=451.1. 1H NMR(400 MHz, DMSO) δ 8.82 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.9 Hz, 2H), 7.74(dd, J=8.6, 2.3 Hz, 1H), 7.58 (s, 1H), 7.10 (d, J=8.5 Hz, 1H), 5.94 (q,J=8.9 Hz, 2H), 4.91 (t, J=5.9 Hz, 1H), 4.57 (dd, J=10.9, 5.6 Hz, 4H),3.51 (d, J=5.9 Hz, 2H), 1.32 (s, 6H)

Example 122(4-(2-hydroxyethyl)piperazin-1-yl)(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone122

Following the procedure for 109,2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 2-(piperazin-1-yl)ethanol gave 122. MS: (ESI+)=492.2. 1H NMR(400 MHz, DMSO) δ 8.39 (d, J=2.0 Hz, 1H), 8.10 (d, J=5.4 Hz, 2H), 7.38(dd, J=8.4, 2.1 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 5.89 (q, J=8.7 Hz, 2H),4.57 (s, 4H), 4.40 (t, J=5.4 Hz, 1H), 4.06 (q, J=5.3 Hz, 1H), 3.51 (dd,J=11.6, 6.0 Hz, 4H), 3.17 (d, J=5.2 Hz, 1H), 2.46-2.39 (m, 5H)

Example 123morpholino(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone123

Following the procedure for 109,2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and morpholine gave 123. MS: (ESI+)=449.1. 1H NMR (400 MHz, DMSO) δ8.42 (d, J=2.0 Hz, 1H), 8.10 (d, J=5.6 Hz, 2H), 7.40 (dt, J=21.4, 10.7Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 5.89 (q, J=8.8 Hz, 2H), 4.57 (s, 4H),3.61 (s, 4H), 3.52 (s, 4H)

Example 124(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)(4-(2,2,2-trifluoroethyl)piperazin-1-yl)methanone124

Following the procedure for 116,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid was reacted with 1-(2,2,2-trifluoroethyl)piperazine dihydrochlorideto give 124 as a white solid. ¹H NMR (CDCl3, 400 MHz): δ 8.02 (d, J=2.1Hz, 1 H); 7.95 (s, 1 H); 7.35 (dd, J=8.3, 2.1 Hz, 1 H); 7.23 (d, J=8.3Hz, 1 H); 6.88 (s, 1 H); 5.73-5.60 (m, 1 H); 4.58 (t, J=5.8 Hz, 2 H);3.94-3.44 (br m, 4H); 3.20 (t, J=5.8 Hz, 2 H); 3.04 (q, J=9.4 Hz, 2 H);2.74 (br s, 4 H); 1.58 (d, J=6.6 Hz, 6 H). LCMS: RT=10.93 min, M+H+=490

Example 125N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-9-carboxamide125

Following the procedure for 126,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid was reacted with 4-amino-1-(2-hydroxyethyl)pyrazole to give 125 asa white solid. ¹H NMR (CDCl3, 400 MHz): δ 8.50 (d, J=2.2 Hz, 1 H); 8.38(s, 1 H); 8.10 (s, 1 H); 7.96 (s, 1 H); 7.78-7.73 (m, 1 H); 7.56 (s, 1H); 7.22 (d, J=8.4 Hz, 1 H); 6.81 (s, 1 H); 5.60-5.47 (m, 1 H); 4.57 (t,J=5.7 Hz, 2 H); 4.23 (t, J=4.8 Hz, 2 H); 4.01 (t, J=4.8 Hz, 2 H); 3.20(t, J=5.7 Hz, 2 H); 1.57 (d, J=6.6 Hz, 6 H). 1 Exchangeable proton notobserved. LCMS: RT=9.27 min, M+H+=449

Example 1262-(1-isopropyl-1H-1,2,4-triazol-5-yl)-N-(isoxazol-3-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-9-carboxamide126

To an ice-cooled suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid (0.15 g, 0.44 mmol) in DCM (3.5 mL) was added oxalyl chloride (79L, 0.93 mmol) and DMF (25 L) and the mixture stirred at RT for 2 h.3-Amino-isoxazole (185 mg, 2.2 mmol) and triethylamine (0.12 mL, 0.88mmol) were added and the mixture stirred at RT for 18 h before theaddition of saturated aqueous sodium hydrogen carbonate. The resultantmixture was extracted with DCM then 5% MeOH in DCM and the combinedextracts dried (Na2SO4), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient0 to 10% MeOH in DCM) followed by trituration in diethyl ether to give126 as a white solid. ¹H NMR (CDCl3, 400 MHz): δ 9.49 (s, 1 H); 8.65 (d,J=2.3 Hz, 1 H); 8.30 (d, J=1.8 Hz, 1 H); 7.96 (d, J=0.7 Hz, 1 H); 7.86(dd, J=8.5, 2.3 Hz, 1 H); 7.30 (d, J=8.5 Hz, 1 H); 7.23 (d, J=1.8 Hz, 1H); 6.88 (s, 1 H); 5.72-5.59 (m, 1 H); 4.61 (t, J=5.6 Hz, 2 H); 3.25 (t,J=5.6 Hz, 2 H); 1.58 (d, J=6.6 Hz, 6 H). LCMS: RT=10.24 min, M+H+=406

Example 127N-(1H-pyrazol-4-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-9-carboxamide127

Following the procedure for 126,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid was reacted with 4-amino-pyrazole-1-carboxylic acid tert-butylester. The intermediate carboxylic acid tert-butyl ester was dissolvedin DCM (5 mL) and treated with TFA (2 mL) before the reaction mixturewas stirred at RT for 2 h. The reaction mixture was concentrated invacuo and the resultant residue triturated in water to give 127 as awhite solid. ¹H NMR (DMSO-d6, 400 MHz): δ 10.53 (s, 1 H); 8.51 (d, J=2.2Hz, 1 H); 8.23 (s, 1 H); 7.96 (dd, J=8.5, 2.2 Hz, 1 H); 7.84 (s, 2 H);7.39 (d, J=8.5 Hz, 1 H); 7.02 (s, 1 H); 5.77 (q, J=8.7 Hz, 2 H); 4.59(t, J=5.8 Hz, 2 H). 3 Protons obscured by water peak. LCMS: RT=9.11 min,M+H+=445

Example 1282-(4-((2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)methyl)piperazin-1-yl)ethanol128

A solution of2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehyde(175 mg, 0.48 mmol) and piperazine ethanol in DCE (15 mL) was treatedwith sodium triacetoxyborohydride (153 mg, 0.72 mmol) and catalyticacetic acid and then stirred at RT for 72 h. The resultant mixture wasdiluted with DCM and washed with saturated aqueous sodium hydrogencarbonate then dried (Na2SO4), filtered and concentrated in vacuo togive a colourless gum which was subjected to flash chromatography (SiO2,gradient 0-10% MeOH in DCM). The appropriate fractions were combined,concentrated in vacuo and the resultant residue dissolved in diethylether and treated with 1M HCl in diethyl ether (2 mL, 2 mmol). Theresultant precipitate was filtered off, washed with ether and dried invacuo to give 128 as a white solid. ¹H NMR (DMSO-d6 plus deuterated TFA,400 MHz): δ 8.22 (s, 1 H); 8.16-8.12 (m, 1 H); 7.66-7.60 (m, 1 H); 7.39(d, J=8.3 Hz, 1 H); 7.02 (s, 1 H); 5.75 (q, J=8.7 Hz, 2 H); 4.57 (t,J=5.9 Hz, 2 H); 4.52 (s, 2 H); 3.76 (t, J=5.0 Hz, 2 H); 3.61 (br s, 8H); 3.32 (s, 2 H); 3.24 (t, J=5.9 Hz, 2 H). 1 Exchangeable not observed.LCMS: RT=6.56 min, M+H+=478

Example 129(4-hydroxypiperidin-1-yl)(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone129

Following the procedure for 109,2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 4-hydroxypiperidine gave 129. MS: (ESI+)=463.1. 1H NMR (400MHz, DMSO) δ 8.39 (d, J=2.0 Hz, 1H), 8.09 (d, J=4.4 Hz, 2H), 7.37 (dd,J=8.4, 2.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 5.87 (q, J=8.5 Hz, 2H), 4.76(d, J=3.8 Hz, 1H), 4.57 (s, 4H), 3.76 (d, J=3.6 Hz, 2H), 1.74 (s, 2H),1.39 (s, 2H)

Example 1309-(piperidin-4-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine130 Step 1:4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert butyl ester

9-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(207 mg, 0.5 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (232 mg, 0.75 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane(10 mol %), and potassium carbonate (138 mg, 1.0 mmol) were charged to areaction vial, the atmosphere evacuated and back-filled with nitrogen.DMF (1 mL) was added, degassing repeated, and the mixture heated at 80°C. for 18 h. The cooled reaction mixture was diluted with ethyl acetateand washed with water then dried (Na2SO4), filtered and concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 20 to 60% ethyl acetate in cyclohexane) to give4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert butyl ester as a white crystalline solid (232 mg, 90%). LCMS:RT=4.87 min, M+H+=517.

A solution of4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert butyl ester (232 mg, 0.41 mmol) in IMS (10 mL) was treatedwith a slurry of Pd/C (170 mg, 10% wt Pd on carbon, 50% water) in IMS.The mixture was degassed then the atmosphere evacuated and back-filledwith hydrogen and then stirred at RT for 18 h. The reaction mixture wasfiltered through Ceilte® with ethyl acetate washings and the filtrateconcentrated in vacuo. The resultant residue was dissolved in methanol(5 mL), treated with 1M HCl in diethyl ether (2 mL, 2 mmol) and themixture stirred at RT for 18 h. Solvent was removed in vacuo and residuetriturated in diethyl ether to give 130 as a pale yellow solid (127 mg,74%). ¹H NMR (DMSO-d6, 400 MHz): δ 9.08-8.97 (br m, 1 H); 8.96-8.81 (brm, 1 H); 8.22 (s, 1 H); 7.69 (s, 1 H); 7.31-7.23 (m, 2 H); 6.99 (s, 1H); 5.72 (q, J=8.8 Hz, 2 H); 4.51 (t, J=6.1 Hz, 2 H); 3.42-3.32 (m, 2H); 3.22-3.15 (m, 2 H); 3.08-2.88 (m, 3 H); 2.04-1.95 (m, 2 H);1.94-1.80 (m, 2 H). LCMS: RT=6.75 min, M+H+=419.2

Example 131N-((2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)methyl)pyrazin-2-amine131

Following the procedure for 128 without the use of HCl in diethyl ether,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehydewas reacted with 2-amino pyrazine to give 131 as a white solid. ¹H NMR(CDCl3, 400 MHz): δ 8.03-7.99 (m, 3 H); 7.87 (d, J=2.6 Hz, 1 H); 7.84(d, J=2.2 Hz, 1 H); 7.31 (dd, J=8.3, 2.2 Hz, 1 H); 7.20 (d, J=8.3 Hz, 1H); 6.92 (s, 1 H); 5.49 (q, J=8.2 Hz, 2 H); 5.42 (br s, 1 H); 4.66 (d,J=5.4 Hz, 2 H); 4.55 (t, J=6.0 Hz, 2 H); 3.16 (t, J=6.0 Hz, 2 H). LCMS:RT=9.93 min, M+H+=443

Example 1322-hydroxy-1-(4-((2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)methyl)piperazin-1-yl)ethanone132

Following the procedure for 128 without the use of HCl in diethyl ether,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehydewas reacted with 2-hydroxy-1-piperazin-1-yl-ethanone to give 132 as awhite solid. ¹H NMR (CDCl3, 400 MHz): δ 7.95 (s, 1 H); 7.86 (d, J=2.0Hz, 1 H); 7.28-7.23 (m, 1 H); 7.17 (d, J=8.2 Hz, 1 H); 6.86 (s, 1 H);5.73-5.60 (m, 1 H); 4.55 (t, J=6.0 Hz, 2 H); 4.15 (s, 2 H); 3.69 (t,J=4.8 Hz, 2 H); 3.64-3.55 (m, 3 H); 3.29 (t, J=4.8 Hz, 2 H); 3.16 (t,J=6.0 Hz, 2 H); 2.55-2.46 (m, 4 H); 1.58 (d, J=6.6 Hz, 6 H). LCMS:RT=5.70 min, M+H+=452

Example 1332-(1-isopropyl-1H-1,2,4-triazol-5-yl)-N-(2-(methylsulfonyl)ethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide133

Methyl2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate184 was saponified to give the corresponding acid,2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (30 mg, 0.09 mmol) which was dissolved in DMF (0.5 mL) and treatedwith diisopropylethylamine (0.077 mL, 0.44 mmol),2-(methylsulfonyl)ethanamine (22 mg, 0.18 mmol) followed by HATU (67 mg,0.18 mmol). The resulting mixture was stirred 12 h at ambienttemperature. Diluted with EtOAc and H2O, extracted the aqueous layerwith EtOAc (2×) and the combined organic portions were washed withbrine, dried over MgSO4, filtered and concentrated in vacuo. The residuewas purified by Prep HPLC to give 133. LC/MS (ESI+): m/z 462 (M+H). 1HNMR (400 MHz, DMSO) δ 8.76 (t, J=5.1, 1H), 8.48 (d, J=8.4, 1H), 7.99 (s,1H), 7.92 (s, 1H), 7.59 (d, J=8.4, 1H), 7.53 (s, 1H), 5.86 (dt, J=13.0,6.6, 1H), 4.56 (d, J=1.9, 4H), 3.69 (dd, J=12.7, 6.5, 2H), 3.39 (t,J=6.7, 2H), 3.05 (d, J=9.0, 3H), 1.49 (d, J=6.6, 5H)

Example 1342-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N-(2-(methylsulfonyl)ethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide134

2-(1-(2-Chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (40 mg, 0.1 mmol) was reacted with 2-(methylsulfonyl)ethanamine toprovide2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N-(2-(methylsulfonyl)ethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide134. LC/MS (ESI+): m/z 514 (M+H). 1H NMR (400 MHz, DMSO) δ 8.72 (s, 1H),8.56 (s, OH), 8.20 (s, 1H), 7.94 (s, 1H), 7.73 (d, J=7.0, 1H), 7.71-7.52(m, 3H), 7.43 (s, 1H), 7.36 (d, J=8.9, 1H), 4.48 (d, J=6.6, 3H),3.73-3.58 (m, 2H), 3.02 (s, 3H)

Example 1352-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide135

Following the procedure for 109,2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 2-amino-2-methylpropan-1-ol gave 135. MS: (ESI+)=479.1. 1H NMR(400 MHz, DMSO) δ 8.19 (s, 1H), 8.11 (d, J=2.2 Hz, 1H), 7.78 (s, 1H),7.71-7.66 (m, 1H), 7.63 (dd, J=7.2, 2.1 Hz, 1H), 7.60-7.50 (m, 3H), 7.37(s, 1H), 6.98 (d, J=8.5 Hz, 1H), 4.99 (t, J=5.9 Hz, 1H), 4.46 (d, J=3.7Hz, 4H), 3.54 (d, J=5.9 Hz, 2H), 1.36 (s, 6H)

Example 136(2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)(4-isopropylpiperazin-1-yl)methanone136

Following the procedure for 109,2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 4-isopropylpiperazine gave 136. MS: (ESI+)=518.2. 1H NMR (400MHz, DMSO) δ 8.20 (s, 1H), 7.84 (s, 1H), 7.70 (s, 2H), 7.64 (d, J=7.4Hz, 1H), 7.62-7.51 (m, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz,1H), 4.48 (s, 4H), 3.57 (s, 2H), 3.04 (s, 2H), 1.29 (d, J=6.5 Hz, 6H)

Example 1372-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide137

Following the procedure for 109,2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 2-amino-2-methylpropan-1-ol gave 137. MS: (ESI+)=481.1. 1H NMR(400 MHz, DMSO) δ 8.26 (d, J=2.2 Hz, 1H), 8.21 (s, 1H), 7.94 (s, 1H),7.73-7.65 (m, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.51-7.42 (m, 1H), 7.39(s, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 4.96 (t, J=6.0Hz, 1H), 4.49 (d, J=6.1 Hz, 4H), 3.52 (d, J=5.8 Hz, 2H), 1.35 (s, 6H)

Example 1382-(4-Cyano-1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide138

Following Example 109,2-(4-Cyano-1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid from Example 16 was coupled with ammonia to give 138. Yield 27.8 mg(44%). MS(ESI):363.1. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=8.4, 1H), 8.11(s, 1H), 8.00 (d, J=4.7, 2H), 7.62 (dd, J=8.4, 1.5, 1H), 7.57 (d, J=1.4,1H), 7.44 (s, 1H), 5.46 (dt, J=13.1, 6.5, 1H), 4.59 (dd, J=17.5, 4.8,4H), 1.48 (d, J=6.6, 6H).

Example 1392-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide139

Following the same procedure as for 133,2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (40 mg, 0.1 mmol) was reacted with methylamine (2M, 0.2 mL) in THFto provide2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide139. LC/MS (ESI+): m/z 422 (M+H). 1H NMR (400 MHz, DMSO) δ 8.43 (d,J=4.5, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.72 (t, J=10.9, 1H), 7.68-7.51(m, 4H), 7.47-7.28 (m, 2H), 4.50 (t, J=15.6, 4H), 2.76 (d, J=4.5, 3H)

Example 140N-(2-hydroxyethyl)-N-isopropyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide140

Following the procedure for 116,8-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acidwas reacted with 2-isopropylamino-ethanol. The intermediate formed (145mg, 0.37 mmol) was dissolved in IMS (10 mL) and triethylamine (50 L,0.37 mmol) then 10% Pd/C (20 mg) added before the reaction mixturestirred under hydrogen (1 atmosphere) for 2.75 h. The reaction mixturewas filtered through Celite® and the filtrate concentrated in vacuo. Theresultant residue was partitioned between DCM and water, the aqueouslayer was isolated and extracted with DCM. The combined organic extractsdried (Na2SO4), filtered and concentrated in vacuo. The resultantresidue was dissolved in diethyl ether and the solution washed withwater, dried (Na2SO4), filtered and then concentrated in vacuo to give140 (79 mg, 68%). ¹H NMR (DMSO-d6, 400 MHz): δ 7.83 (dd, J=8.0, 1.6 Hz,1 H); 7.30 (td, J=7.6, 1.8 Hz, 1 H); 7.26-7.16 (m, 2 H); 6.54 (s, 1 H);4.67-4.53 (m, 1 H); 4.46 (t, J=6.0 Hz, 2 H); 4.35-4.27 (m, 1 H);3.64-3.56 (m, 2 H); 3.55-3.46 (m, 2 H); 3.13 (t, J=6.0 Hz, 2 H); 1.22(d, J=6.8 Hz, 6 H). LCMS: RT=9.00 min, M+H+=316

Example 1414-((2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)methyl)piperazin-2-one141

Following the procedure for 128 without the use of HCl in diethyl ether,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehydewas reacted with 2-hydroxy-1-piperazin-1-yl-ethanone to give 141 as awhite solid. ¹H NMR (MeOD, 400 MHz): δ 8.00 (s, 1 H); 7.92 (d, J=2.1 Hz,1 H); 7.34 (dd, J=8.3, 2.1 Hz, 1 H); 7.22 (d, J=8.3 Hz, 1 H); 6.88 (s, 1H); 5.80-5.67 (m, 1 H); 4.54 (t, J=6.1 Hz, 2 H); 3.69 (s, 2 H);3.36-3.28 (m, 2 H); 3.19 (t, J=6.1 Hz, 2 H); 3.13 (s, 2 H); 2.76-2.70(m, 2 H); 1.56 (d, J=6.6 Hz, 6 H). 1 Exchangeable proton not observed.LCMS: RT=7.45 min, M+H+=408

Example 1422-(4-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)piperidin-1-yl)ethanol142

A mixture of9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(180 mg, 0.43 mmol) in DMF (1 mL), potassium carbonate (89 mg, 0.65mmol) and 2-(2-bromo-ethoxy)-tetrahydro-pyran (97 L, 0.65 mmol) washeated at 50° C. for 18 h. The cooled reaction mixture was partitionedbetween ethyl acetate and water, the aqueous layer extracted with ethylacetate and the combined organic extracts dried (Na2SO4), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0 to 10% MeOH (+2M NH3) in DCM) to give acolourless oil. The oil was dissolved in methanol and treated with 1MHCl in methanol (2 mL, 2 mmol) and the reaction mixture stirred for 2 hat RT before concentrating in vacuo. The resultant residue wastriturated in a mixture of diethyl ether and methanol to give 142 as apale yellow solid (115 mg, 54%). ¹H NMR (DMSO-d6, 400 MHz): δ 9.81 (brs, 1 H); 8.22 (s, 1 H); 7.70 (s, 1 H); 7.32-7.24 (m, 2 H); 6.99 (s, 1H); 5.72 (q, J=8.7 Hz, 2 H); 5.36 (br s, 1 H); 4.51 (t, J=6.0 Hz, 2 H);3.80 (t, J=4.9 Hz, 2 H); 3.67-3.57 (m, 2 H); 3.22-3.06 (m, 6 H);2.97-2.85 (m, 1 H); 2.10-2.00 (m, 4 H). LCMS: RT=6.62 min, M+H+=463.1

Example 1432-(4-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide143

A mixture of9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(180 mg, 0.43 mmol) in DMF (1 mL) was treated with potassium carbonate(89 mg, 0.65 mmol) and bromo acetamide (77 mg, 0.56 mmol) and thenstirred at RT for 18 h. The reaction mixture was partitioned betweenethyl acetate and water, the aqueous layer extracted with ethyl acetateand the combined organic extracts dried (Na2SO4), filtered andconcentrated in vacuo. The resultant residue was triturated in diethylether to give 143 as a pale yellow solid (115 mg, 54%). ¹H NMR (DMSO-d6,400 MHz): δ 8.21 (s, 1 H); 7.75 (d, J=2.2 Hz, 1 H); 7.28 (dd, J=8.4, 2.2Hz, 1 H); 7.20 (d, J=8.3 Hz, 1 H); 7.15 (s, 2 H); 6.97 (s, 1 H); 5.73(q, J=8.8 Hz, 2 H); 4.49 (t, J=6.0 Hz, 2 H); 3.20 (t, J=6.0 Hz, 2 H);2.96-2.85 (m, 4 H); 2.62-2.52 (m, 1 H); 2.24-2.14 (m, 2 H); 1.84-1.66(m, 4 H). LCMS: RT=6.55 min, M+H+=476

Example 1449-(azetidin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine144

9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(0.52 g, 1.40 mmol) and 3-azetidine-1-carboxylic acid tert-butyl esterzinc iodide (2.0 mmol) were reacted to give3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidine-1-carboxylicacid tert-butyl ester (0.47 g, 49%). LCMS RT=4.70 M+H+=451.

9-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(0.41 g, 0.76 mmol) was treated with acid to give the crudehydrochloride salt which was partitioned between ethyl acetate andsaturated aqueous sodium hydrogen carbonate and extracted three timeswith DCM. The combined extracts were dried (Na2SO4), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0 to 10% 2M NH3 (in MeOH) in DCM) to give144 (162 mg, 31%). ¹H NMR (400 MHz, CDCl3): δ 7.97-7.93 (m, 1 H); 7.82(d, J=2.19 Hz, 1 H); 7.29 (dd, J=8.36, 2.25 Hz, 1 H); 7.19 (d, J=8.32Hz, 1 H); 6.87 (s, 1 H); 5.74-5.66 (m, 1 H); 4.57-4.50 (m, 2 H);4.12-4.02 (m, 1 H); 4.00 (t, J=7.46 Hz, 2 H); 3.87 (t, J=7.27 Hz, 2 H);3.16 (t, J=6.02 Hz, 2 H); 1.62 (d, 6 H). LCMS: RT=6.01 min, M+H+=351

Example 1452-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(piperazine-1-carbonyl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole145

A mixture of N-Boc piperazine (101 mg, 0.54 mmol),2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene-9-carboxylicacid (180 mg, 0.53 mmol), EDCI (151 mg, 0.79 mmol), HOBt (107 mg, 0.795mmol) and triethylamine (216 L, 1.54 mmol) in DMF (2 mL) was stirred atRT for 20 h. The mixture was diluted with ethyl acetate and washed(water, saturated aqueous sodium hydrogen carbonate and then brine),dried (Na2SO4), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0 to 10%MeOH in DCM) to give4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene-9-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester (258 mg, 96%). The intermediate carboxylic acidtert-butyl ester was dissolved in DCM (20 mL) and treated with 4N HCl indioxane (4 mL) and stirred for 3 h at RT before adding diethyl ether (20mL). The resultant precipitate was collected by filtration and washedwith diethyl ether to give 145 as a white solid (209 mg, 93%). ¹H NMR(400 MHz, DMSO-d): δ 9.32 (s, 2 H); 8.37 (s, 1 H); 8.31 (d, J=2.20 Hz, 1H); 8.06 (s, 1 H); 7.44 (dd, J=8.37, 2.21 Hz, 1 H); 7.15 (d, J=8.37 Hz,1 H); 5.32-5.23 (m, 1 H); 4.37 (t, J=4.98 Hz, 2 H); 3.77 (s, 4 H); 3.15(t, J=6.94 Hz, 6 H); 1.51 (d, J=6.59 Hz, 6 H). LCMS: RT=6.02 min,M+H+=408

Example 1462-(4-isopropyl-4H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole146 Step 1: 4-Isopropyl-3-methylsulfanyl-4H-[1,2,4]triazole

To a solution of 4-isopropyl-3-thiosemicarbazide (7.0 g, 52.54 mmol) indioxane (50 ml) was added DMF-DMA (14.1 ml, 105.08 mmol) and the mixtureheated to 100° C. After 3 h additional DMF-DMA (52.54 mmol) was addedand heating was continued. After 18 h the mixture was allowed to cool toRT and the solvent removed in vacuo. The resultant residue was subjectedto flash chromatography (SiO2, gradient 0 to 100% ethyl acetate incyclohexane) to afford 4-Isopropyl-3-methylsulfanyl-4H-[1,2,4]triazole(4.05 g, 49%) LCMS RT=2.55 min, M+H+=158.

Step 2: 4-Isopropyl-3-methanesulfonyl-4H-[1,2,4]triazole

To a solution of 4-isopropyl-3-methylsulfanyl-4H-[1,2,4]triazole (3.05g, 19.43 mmol) in DCM (30 ml) was added formic acid (2.9 ml, 76.36 mmol)and ammonium molybdate tetrahydrate (56 mg, 0.047 mmol). To the rapidlystirring mixture was carefully added hydrogen peroxide solution (50 wt.% in H2O, 8 mL, 116.58 mmol) in portions to avoid uncontrolled exotherm.After complete addition the mixture was stirred at RT for 18 h. Themixture was cooled in an ice bath and carefully quenched with saturatedsodium sulfite solution, then extracted with DCM (3×100 mL). The organicextracts were combined and dried (Na2SO4), filtered and concentrated invacuo to afford 4-Isopropyl-3-methanesulfonyl-4H-[1,2,4]triazole (3.29g, 90%) LCMS RT=2.02 min, M+H+=190.

Step 3:9-bromo-2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene

To a microwave vial were charged9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (200 mg, 0.755mmol), 4-isopropyl-3-methanesulfonyl-4H-[1,2,4]triazole (143 mg, 0.755mmol), cesium carbonate (246 mg, 0.755 mmol) and THF (2 mL). Thereaction mixture was heated to 150° C. for 2 h then extracted with ethylacetate (20 mL), washed with water (20 mL), dried (Na2SO4), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0 to 100% ethyl acetate in cyclohexane)to afford9-bromo-2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(122 mg, 43%). LCMS RT=4.34 min, M+H+=374/376.

Step 4:2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene

To a degassed solution of9-bromo-2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(122 mg, 0.326 mmol) in IMS (10 mL) was added TEA (51 L, 0.359 mmol) and10% Pd/C (15 mg). The mixture was stirred under hydrogen (1 atmosphere)for 60 min then filtered, and the filtrate concentrated in vacuo. Theresultant residue was dissolved in DCM (20 mL) and washed with water (20mL), the organic layer dried (Na2SO4), filtered and concentrated invacuo. The resultant residue was freeze dried from acetonitrile andwater to afford 146 (54 mg, 56%). LCMS: RT=10.29 min, M+H+=296.

Alternatively, a degassed solution of8-bromo-2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(122 mg, 0.326 mmol) in IMS (10 mL) was added 10% Pd/C (15 mg), thereaction mixture stirred under an atmosphere of hydrogen for 1 h beforethe reaction mixture was filtered and the filtrate concentrated invacuo. The resultant residue was dissolved in DCM and the solutionwashed with water, the organic layer dried (Na2SO4), filtered andconcentrated in vacuo to give a residue. The residue was dissolved inacetonitrile and water and the solution freeze dried to give2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azuleneas a white solid (54 mg, 56%). ¹H NMR (400 MHz, CDCl3): δ 8.27-8.23 (m,2 H); 8.12 (t, J=1.02 Hz, 1 H); 7.30-7.24 (m, 1 H); 7.14-7.06 (m, 2 H);5.38-5.29 (m, 1 H); 4.36 (t, J=5.10 Hz, 2 H); 3.16 (td, J=5.10, 1.06 Hz,2 H); 1.63-1.54 (d, J=6.59 Hz, 6 H). LCMS: RT=10.29 min, M+H+=296

Example 1472-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole-9-carboxamide147

Following the procedure for 116,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene-9-carboxylicacid was reacted with 4-amino-1-(2-hydroxyethyl)pyrazole to give 147 asa white solid. ¹H NMR (400 MHz, DMSO-d): δ 10.45 (s, 1 H); 8.85 (d,J=2.32 Hz, 1 H); 8.36 (s, 1 H); 8.08-8.05 (m, 2 H); 7.87 (dd, J=8.53,2.35 Hz, 1 H); 7.58 (d, J=0.69 Hz, 1 H); 7.18 (d, J=8.50 Hz, 1 H);5.36-5.28 (m, 1 H); 4.88 (t, J=5.31 Hz, 1 H); 4.39 (t, J=4.97 Hz, 2 H);4.13 (t, J=5.61 Hz, 2 H); 3.73 (q, J=5.51 Hz, 2 H); 3.16 (t, J=4.96 Hz,2 H); 1.53 (d, J=6.59 Hz, 6 H). LCMS: RT=9.63 min, M+H+=449

Example 1482-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(methylsulfonyl)azetidin-3-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine148

An ice-cooled solution of9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(0.16 g, 0.46 mmol) in DCM (5 mL) was treated with triethylamine (0.14mL, 1.0 mmol) then methanesulfonyl chloride (40 L, 0.51 mmol) and themixture stirred at RT for 2 h. The reaction mixture was washed withwater and the aqueous layer extracted with DCM, the combined organicextracts were combined, dried (Na2SO4), filtered and concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 50 to 100% ethyl acetate in cyclohexane) to give 148 asa white solid (126 mg, 64%). ¹H NMR (400 MHz, CDCl3): δ 7.95 (d, J=2.49Hz, 2 H); 7.31 (dd, J=8.35, 2.29 Hz, 1 H); 7.21 (d, J=8.32 Hz, 1 H);6.89 (s, 1 H); 5.75-5.66 (m, 1 H); 4.56 (t, J=5.89 Hz, 2 H); 4.32 (t,J=8.24 Hz, 2 H); 4.12 (t, J=7.34 Hz, 2 H); 3.92-3.82 (m, 1 H); 3.20 (t,J=5.89 Hz, 2 H); 2.93 (s, 3 H); 1.62 (d, 6 H). LCMS: RT=9.68 min,M+H+=429

Example 1491-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)azetidin-1-yl)ethanone149

Following the procedure for 148,9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulenewas reacted with acetic anhydride to give 149 as a white solid. ¹H NMR(400 MHz, CDCl3): δ 7.93 (s, 1 H); 7.85 (d, J=2.17 Hz, 1 H); 7.27-7.20(m, 1 H); 7.19 (d, J=8.32 Hz, 1 H); 6.85 (s, 1 H); 5.68-5.59 (m, 1 H);4.59-4.50 (m, 3 H); 4.44 (t, J=9.38 Hz, 1 H); 4.18-4.11 (m, 1 H);4.13-4.05 (m, 1 H); 3.89-3.80 (m, 1 H); 3.16 (t, J=5.93 Hz, 2 H); 1.91(s, 3 H); 1.57 (d, J=6.62 Hz, 6 H). LCMS: RT=9.50 min, M+H+=393

Example 1502-hydroxy-1-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)azetidin-1-yl)ethanone150

Following the procedure for 116,9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulenewas reacted with glycolic acid to give 150 as a white solid. ¹H NMR (400MHz, CDCl3): δ 7.95 (s, 1 H); 7.87 (d, J=2.09 Hz, 1 H); 7.28-7.21 (m, 1H); 7.24-7.19 (m, 1 H); 6.87 (s, 1 H); 5.68-5.59 (m, 1 H); 4.60-4.48 (m,4 H); 4.20 (dd, J=9.89, 6.11 Hz, 1 H); 4.16-4.07 (m, 1 H); 4.05 (d,J=3.28 Hz, 2 H); 4.03-3.96 (m, 1 H); 3.18 (t, J=5.91 Hz, 2 H); 1.58 (d,J=6.62 Hz, 6 H). 1 Exchangeable proton not observed. LCMS: RT=8.95 min,M+H+=409

Example 1512-hydroxy-1-(4-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)piperidin-1-yl)ethanone151

Following the procedure for 116,9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulenewas reacted with glycolic acid to give 151 as a white solid. ¹H NMR (400MHz, DMSO-d): δ 8.21 (s, 1 H); 7.73 (d, J=2.16 Hz, 1 H); 7.29 (dd,J=8.37, 2.17 Hz, 1 H); 7.21 (d, J=8.32 Hz, 1 H); 6.97 (s, 1 H); 5.72 (q,J=8.78 Hz, 2 H); 4.55-4.43 (m, 4 H); 4.13-4.05 (m, 2 H); 3.79 (d,J=13.44 Hz, 1 H); 3.23-3.15 (m, 3 H); 3.09 (t, J=12.91 Hz, 1 H);2.91-2.82 (m, 1 H); 2.77-2.65 (m, 1 H); 1.86 (d, J=12.87 Hz, 2 H). LCMS:RT=9.76 min, M+H+=477

Example 1529-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine152

A mixture of9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(90 mg, 0.22 mmol), triethylamine (150 L, and IMS (0.6 mL) was treatedwith vinyl sulfone (48 mL, 0.54 mmol) then diluted with DCM and stirredfor 18 h at RT. The reaction mixture was concentrated in vacuo and theresidue triturated in diethyl ether to provide a solid which wassubjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM)to give 152 as a white solid (96 mg, 85%). ¹H NMR (400 MHz, CDCl3): δ8.01 (s, 1 H); 7.69 (s, 1 H); 7.19-7.08 (m, 2 H); 6.92 (s, 1 H); 5.53(q, J=8.15 Hz, 2 H); 4.54 (t, J=6.01 Hz, 2 H); 3.21-3.12 (m, 4 H);3.21-2.92 (m, 5 H); 2.93 (t, J=6.33 Hz, 2 H); 2.63-2.54 (m, 1 H); 2.21(t, J=11.57 Hz, 2 H); 1.94 (d, J=12.96 Hz, 2 H); 1.81-1.66 (m, 2 H).LCMS: RT=6.57 min, M+H+=525

Example 153 ((3S,5R)-3,5-dimethylpiperazin-1-yl)(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)methanone153

Following the procedure for 109,2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 3S,5R-dimethylpiperazine gave 153. MS: (ESI+)=476.1. 1H NMR(400 MHz, DMSO) δ 8.39 (d, J=2.0 Hz, 1H), 8.10 (d, J=4.9 Hz, 2H), 7.37(dd, J=8.4, 2.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 5.88 (s, 2H), 4.57 (s,4H), 4.06 (q, J=5.3 Hz, 2H), 3.17 (d, J=5.2 Hz, 2H), 2.67 (s, 2H), 0.92(s, 6H)

Example 1542-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-9-piperid-4-yl-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole154 Step 1:4-{2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

4-{2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester was prepared similarly to4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester from9-bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene(500 mg, 1.13 mmol) to give4-{2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester as a colourless gum (490 mg, 80%). LCMS RT=5.14min, M+Na+=567

Step 2:2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene

2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenewas prepared similarly to9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulenefrom4-{2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (490 mg, 0.9 mmol). The crude salt was partitionedbetween DCM and saturated aqueous sodium hydrogen carbonate, then theaqueous layer was extracted with DCM. The combined organic extracts weredried (Na2SO4), filtered and concentrated in vacuo. The resultantresidue was subjected to reverse phase HPLC (Gemini C18 column, gradientMeOH in H2O+0.1% HCO2H) to give 154 (80 mg, 18%) as the mono formatesalt. ¹H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1 H); 8.39 (s, 1 H); 8.27(s, 1 H); 7.81-7.68 (m, 3 H); 7.64 (td, J=7.60, 1.51 Hz, 1 H); 7.09-7.03(m, 2 H); 6.90 (d, J=8.28 Hz, 1 H); 4.19 (t, J=5.06 Hz, 2 H); 3.32 (d,J=12.42 Hz, 2 H); 3.04 (t, J=5.01 Hz, 2 H); 2.89 (dd, J=13.45, 11.09 Hz,2 H); 2.54-2.56 (m, 1 H); 1.69 (d, J=13.20 Hz, 2 H); 1.58-1.45 (m, 2 H).LCMS: RT=7.99 min, M+H+=447

Example 1552-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)azetidin-1-yl)acetamide155

Following the procedure for 143,9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulenewas reacted with bromo acetamide and the crude product subjected flashchromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 155 as awhite solid. ¹H NMR (400 MHz, CDCl3): δ 7.95 (s, 1 H); 7.83 (d, J=2.18Hz, 1 H); 7.24 (d, J=2.21 Hz, 1 H); 7.18 (d, J=8.31 Hz, 1 H); 6.86 (s, 1H); 5.71-5.63 (m, 1 H); 5.45 (s, 1 H); 4.54 (t, J=5.98 Hz, 2 H); 3.87(t, J=7.28 Hz, 2 H); 3.81-3.72 (m, 1 H); 3.38 (t, J=6.84 Hz, 2 H); 3.22(s, 2 H); 3.16 (t, J=5.99 Hz, 2 H); 1.59 (d, J=6.62 Hz, 6 H). 1Exchangeable proton not observed. LCMS: RT=5.84 min, M+H+=408

Example 156N-(azetidin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-9-carboxamide156

Following the procedure for 126,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid was reacted with 1,1-dimethylethyl 3-aminoazetidine-1-carboxylatethen the crude product was suspended in DCM and treated with MPcarbonate resin and stirred for 1.5 h. The mixture was filtered, thefiltrate concentrated in vacuo and the resultant residue triturated indiethyl ether to give 156 as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ9.11 (d, J=6.84 Hz, 1 H); 8.46 (d, J=2.18 Hz, 1 H); 8.05 (t, J=0.64 Hz,1 H); 7.90-7.85 (m, 1 H); 7.37-7.30 (m, 1 H); 6.92 (s, 1 H); 5.62-5.53(m, 1 H); 4.82-4.73 (m, 1 H); 4.57 (t, J=5.76 Hz, 2 H); 3.95-3.81 (m, 4H); 3.25 (t, J=5.78 Hz, 2 H); 1.50 (d, J=6.58 Hz, 6 H). LCMS RT=6.45min, M+H+=394

Example 1572-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(methylsulfonyl)ethyl)azetidin-3-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine157

Following the procedure for 152,9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulenewas reacted with vinyl sulfone to give 157 as a white solid. ¹H NMR (400MHz, DMSO-d6): δ 8.01 (d, J=0.64 Hz, 1 H); 7.84 (d, J=2.19 Hz, 1 H);7.36 (dd, J=8.32, 2.21 Hz, 1 H); 7.21 (d, J=8.30 Hz, 1 H); 6.87 (s, 1H); 5.60-5.51 (m, 1 H); 4.48 (t, J=6.03 Hz, 2 H); 3.67 (s, 3 H);3.20-3.10 (m, 6 H); 3.03 (s, 3 H); 2.83 (t, J=6.83 Hz, 2 H); 1.48 (d,J=6.58 Hz, 6 H). LCMS: RT=5.99 min, M+H+=457

Example 158N-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide158

Following the same procedure as for 133,2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (60 mg, 0.1 mmol) was reacted with 2M methylamine (0.26 mL) in THFto provide 158. LC/MS (ESI+): m/z 393 (M+H). 1H NMR (400 MHz, DMSO) δ8.49 (d, J=4.2, 1H), 8.42 (s, 1H), 8.11 (d, J=9.8, 1H), 7.60 (dd, J=8.4,1.6, 1H), 7.52 (d, J=1.4, 1H), 5.90 (q, J=8.8, 2H), 4.57 (dd, J=11.5,5.4, 4H), 2.79 (d, J=4.5, 3H).

Example 1592-(1-isopropyl-1H-1,2,4-triazol-5-yl)-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide159

Following the same procedure as for 133,2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (100 mg, 0.3 mmol) was reacted with 2M methylamine (0.59 mL) in THFto provide 159. LC/MS (ESI+): m/z 353 (M+H). 1H NMR (400 MHz, DMSO) δ8.54-8.39 (m, 1H), 7.93 (dd, J=18.0, 11.2, 1H), 7.67-7.46 (m, −1H), 6.47(d, J=33.7, −2H), 5.94-5.78 (m, −2H), 4.68-4.47 (m, −4H), 3.52-3.55 (s,−3H), 2.90-2.68 (m, 1H), 1.47 (t, J=13.6, 6H).

Example 1602-(1-isopropyl-1H-1,2,4-triazol-5-yl)-10-(1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine160

Following Example 182,10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine187 was coupled with tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateto give 160. MS: 362.3. 1H NMR (400 MHz, DMSO) δ 8.57 (t, J=4.0, 1H),7.99-7.94 (m, 4H), 7.56 (dt, J=11.2, 5.6, 1H), 7.06 (t, J=8.6, 1H), 5.81(p, J=6.6, 1H), 4.53 (d, J=9.5, 4H), 1.53 (d, J=6.6, 7H).

Example 1612-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide161

Following the procedure for 109,2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 2-amino-2-methylpropan-1-ol gave 161. MS: (ESI+)=478.1. 1H NMR(400 MHz, DMSO) δ 8.12 (d, J=2.1 Hz, 1H), 7.63 (dd, J=6.0, 3.4 Hz, 1H),7.53 (dd, J=6.1, 3.2 Hz, 2H), 7.50-7.44 (m, 3H), 7.36 (s, 1H), 7.28 (d,J=1.1 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 5.00 (s, 1H), 4.41(s, 4H), 3.55 (d, J=5.1 Hz, 2H), 1.36 (s, 6H)

Example 162(2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone162

Following the procedure for 109,2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and 2-(piperazin-1-yl)ethanol gave 162. MS: (ESI+)=522.2

Example 163N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide163

Following the same procedure as for 133,2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (20 mg, 0.06 mmol) was reacted with 2-amino-2-methyl-1-propanol (11mg, 0.12 mmol) in THF to provideN-(1-hydroxy-2-methylpropan-2-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide163. LC/MS (ESI+): m/z 411 (M+H). 1H NMR (400 MHz, DMSO) δ 8.45 (d,J=8.4, 1H), 7.95 (d, J=22.3, 2H), 7.64-7.45 (m, 3H), 5.86 (dt, J=13.1,6.5, 1H), 4.88 (t, J=6.0, 1H), 4.63-4.44 (m, 4H), 3.58-3.45 (m, 3H),1.49 (d, J=6.6, 6H), 1.32 (s, 6H)

Example 164N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-(S-dioxo-tetrahydrothiophen-3-yl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxamide164

Following the procedure for 109,2-(1-(S-dioxo-tetrahydrothiophen-3-yl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylicacid and amino-2-methylpropan-1-ol gave 164. MS: (ESI+)=487.1

Example 1652-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide165

Following the same procedure as for 133,2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (20 mg, 0.06 mmol) was reacted with 2-amino-2-methyl-1-propanol (11mg, 0.12 mmol) in THF to provide 165. LC/MS (ESI+): m/z 480 (M+H). 1HNMR (400 MHz, DMSO) δ 8.19 (s, 1H), 7.93 (s, 1H), 7.78-7.48 (m, 6H),7.43-7.26 (m, 2H), 4.85 (t, J=6.1, 1H), 4.47 (d, J=9.0, 4H), 3.49 (d,J=6.0, 2H), 1.29 (s, 6H)

Example 1662-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(pyridin-4-ylmethyl)azetidin-3-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine166

Following the procedure for 128,9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulenewas reacted with pyridine 4-carboxaldehyde, the crude product subjectedflash chromatography (SiO2, gradient 0 to 20% MeOH in ethyl acetate)then trituration in cyclohexane to give 166 as a white solid. ¹H NMR(400 MHz, CDCl3): δ 8.55 (d, J=5.20 Hz, 2 H); 7.95 (s, 1 H); 7.86 (d,J=2.20 Hz, 1 H); 7.30-7.24 (m, 3 H); 7.21-7.12 (m, 1 H); 6.88-6.83 (m, 1H); 5.73-5.65 (m, 1 H); 4.54 (t, J=5.99 Hz, 2 H); 3.89-3.74 (m, 3 H);3.71 (s, 2 H); 3.30 (s, 2 H); 3.16 (t, J=5.99 Hz, 2 H); 1.58 (d, J=6.62Hz, 6 H). LCMS: RT=6.07 min, M+H+=442

Example 1672-(1-isopropyl-1H-1,2,4-triazol-5-yl)-N-(1-isopropylazetidin-3-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-9-carboxamide167

A solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylicacid azetidin-3-ylamide (0.15 g, 0.38 mmol), acetone (84 L, 1.14 mmol),acetic acid (22 L), methanol (1 mL) and DCM (1 mL) was stirred at RT for1 h. Sodium triacetoxyborohydride (0.2 g, 0.95 mmol) was added and theresultant mixture stirred at RT for 72 h. Further acetone (84 L) and 4 Åmolecular sieves were added then stirring continued for 1 h before theaddition of further sodium triacetoxyborohydride (0.2 g, 0.95 mmol). Thereaction mixture was stirred at RT for 18 h before the addition ofsaturated aqueous sodium hydrogen carbonate. The resultant mixture wasextracted with 10% MeOH in DCM. The combined extracts were dried(Na2SO4), filtered and concentrated in vacuo. The resultant residue wassubjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM)followed by trituration in diethyl ether and recrystallisation in ethylacetate to give 167 as a white solid. ¹H NMR (400 MHz, CDCl3): δ 8.47(d, J=2.22 Hz, 1 H); 7.95 (s, 1 H); 7.71 (dd, J=8.44, 2.24 Hz, 1 H);7.23 (d, J=8.43 Hz, 1 H); 6.87 (s, 1 H); 5.72-5.64 (m, 1 H); 4.74-4.67(m, 1 H); 4.58 (t, J=5.67 Hz, 2 H); 3.68 (t, J=7.42 Hz, 2 H); 3.22 (t,J=5.69 Hz, 2 H); 3.12 (s, 2 H); 2.38 (t, J=7.02 Hz, 1 H); 1.61 (d,J=6.61 Hz, 6 H); 0.98 (d, J=6.21 Hz, 6 H). LCMS: RT=6.82 min, M+H+=436

Example 1682-(1-isopropyl-1H-1,2,4-triazol-5-yl)-N-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide168

Following the same procedure as for 133,2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (20 mg, 0.06 mmol) was reacted with Methoxylamine hydrochloride(9.8 mg, 0.12 mmol) in THF to provide 168. LC/MS (ESI+): m/z 369 (M+H).1H NMR (400 MHz, DMSO) δ 8.45 (t, J=16.8, 1H), 7.95 (d, J=26.9, 2H),7.49 (dd, J=20.1, 18.6, 2H), 5.86 (dt, J=13.1, 6.4, 1H), 4.56 (d, J=2.8,4H), 3.72 (s, 2H), 1.61-1.32 (m, 5H)

Example 1692-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)azetidin-1-yl)ethanol169

Following the procedures of Example 142,9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene144 was reacted with 2-(2-bromoethoxy)-tetrahydropyran followed byacidic hydrolysis of the THP group to give 169 as a white solid, asillustrated in FIG. 13. ¹H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1 H); 7.88(d, J=2.22 Hz, 1 H); 7.42 (dd, J=8.35, 2.22 Hz, 1 H); 7.26 (d, J=8.32Hz, 1 H); 6.89 (s, 1 H); 5.62-5.54 (m, 1 H); 4.83 (s, 1 H); 4.50 (t,J=6.03 Hz, 2 H); 4.06 (s, 2 H); 3.94 (t, J=8.52 Hz, 1 H); 3.70 (s, 2 H);3.51 (s, 3 H); 3.18 (t, J=6.05 Hz, 2 H); 2.94 (s, 2 H); 1.49 (d, J=6.58Hz, 6 H). LCMS: RT=6.01 min, M+H+=395

Example 1702-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepin-9-yl)azetidin-1-yl)-2-methylpropan-1-ol170

A mixture of9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene(200 mg, 0.55 mmol), 2-bromo-2-methyl propionate (71 L, 0.55 mmol),triethylamine (75 L, 0.55 mmol) in DMF was heated at 55° C. for 30 hbefore concentrating in vacuo. The residue was partitioned between 10%MeOH in DCM and water, the aqueous extracted with 10% MeOH in DCM andthe combined organic extracts dried (Na2SO4), filtered and concentratedin vacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 0 to 10% MeOH in DCM) to give2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propionicacid methyl ester 63 (56 mg, 23%). To a solution of2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propionicacid methyl ester 63 (56 mg, 0.12 mmol) in THF (1.5 mL) at −78° C. wasadded DIBAL (1.5 M solution in toluene, 0.24 mL, 0.36 mmol) and themixture allowed to warm to RT over 18 h. The mixture was cooled to 0°C., further DIBAL (0.12 mL, 0.18 mmol) added dropwise and stirringcontinued for 45 min. The reaction was quenched by the addition of MeOH(0.5 mL) followed by Rochelle's salt saturated aqueous solution (0.5mL), then diluted with ethyl acetate and filtered through Celite®,washing with ethyl acetate. The filtrate was concentrated in vacuo andthe residue subjected to flash chromatography (SiO2, gradient 0 to 5%MeOH (+2M NH3) in DCM) to give 170 as a white solid, as illustrated inFIG. 13 (27 mg, 53%). ¹H NMR (400 MHz, CDCl3): δ 7.95 (s, 1 H); 7.85 (d,J=2.18 Hz, 1 H); 7.23 (d, J=2.23 Hz, 1 H); 7.17 (d, J=8.29 Hz, 1 H);6.87 (s, 1 H); 5.74-5.66 (m, 1 H); 4.55 (t, J=6.02 Hz, 2 H); 3.71 (s, 3H); 3.43 (s, 2 H); 3.28 (s, 2 H); 3.16 (t, J=6.03 Hz, 2 H); 1.59 (d,J=6.62 Hz, 6 H); 1.04 (s, 6 H). 1 Exchangeable proton not observed.LCMS: RT=6.43 min, M+H+=423

Example 1712-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-8-(1-(2-(methylsulfonyl)ethyl)azetidin-3-yl)-4,5-dihydrobenzo-2H-oxepino[4,5-d]pyrazole171

Following the procedure for 152,8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride was reacted with vinyl sulfone. The crude product wassubjected to reverse phase HPLC (Gemini C6-phenyl column, gradient 40 to90% methanol in water+0.1% HCO2H) to give 171 as a white solid. ¹H NMR(400 MHz, DMSO-d6): δ 8.42 (s, 1 H); 8.29 (s, 1 H); 8.14 (s, 1 H); 7.81(td, J=8.75, 5.92 Hz, 1 H); 7.64 (ddd, J=10.33, 9.02, 2.80 Hz, 1 H);7.38-7.32 (m, 1 H); 7.29 (d, J=8.17 Hz, 1 H); 6.96 (d, J=1.71 Hz, 1 H);6.91 (dd, J=8.25, 1.80 Hz, 1 H); 4.23 (t, J=5.01 Hz, 2 H); 3.66 (t,J=7.11 Hz, 2 H); 3.76-3.41 (m, 1 H); 3.16 (t, J=7.36 Hz, 5 H); 3.05 (s,4 H); 2.88 (t, J=6.91 Hz, 2 H). LCMS: RT=7.25 min, M+H+=527

Example 1722-(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidin-1-yl)-acetamide172

Following the procedure for 143,8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride was reacted with bromo acetamide, the crude product wassubjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM)to give 172 as a white solid. ¹H NMR (400 MHz, DMSO-d): δ 8.42 (s, 1 H);8.28 (s, 1 H); 7.81 (td, J=8.75, 5.92 Hz, 1 H); 7.63 (ddd, J=10.33,9.01, 2.79 Hz, 1 H); 7.39-7.27 (m, 2 H); 7.11 (s, 1 H); 7.03 (s, 1 H);6.96-6.89 (m, 2 H); 4.23 (t, J=5.01 Hz, 2 H); 3.66 (t, J=7.02 Hz, 2 H);3.62-3.52 (m, 1 H); 3.16 (t, J=6.65 Hz, 2 H); 3.10-2.98 (m, 4 H). LCMS:RT=7.00 min, M+H+=478

Example 173N-hydroxy-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide173

Following the same procedure as for 133,2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (20 mg, 0.06 mmol) was reacted with hydroxylamine hydrochloride (8mg, 0.1 mmol) in THF to provide 173. LC/MS (ESI+): m/z 355 (M+H)

Example 1742-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide174

Following the same procedure as for 133,2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (30 mg, 0.07 mmol) was reacted with 2M methylamine (0.06 mL) in THFto provide 174. LC/MS (ESI+): m/z 422 (M+H). 1H NMR (400 MHz, DMSO) δ8.52 (t, J=9.7, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.80-7.67 (m, 2H),7.67-7.55 (m, 1H), 7.47-7.38 (m, 2H), 7.33 (t, J=8.4, 1H), 4.50 (d,J=7.7, 3H), 2.74 (t, J=17.2, 3H)

Example 1752-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene175

Following the procedure for 152,2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride was reacted with vinyl sulfone. The crude product wasdissolved in DCM and treated with 4N HCl. After stirring for 10 mindiethyl ether was added and the solid precipitate collected byfiltration to give 175 as a white solid. ¹H NMR (400 MHz, DMSO-d): δ10.63 (s, 1 H); 8.45 (s, 1 H); 8.30 (s, 1 H); 7.85 (td, J=8.75, 5.90 Hz,1 H); 7.72 (t, J=9.62 Hz, 1 H); 7.42 (t, J=8.57 Hz, 1 H); 7.22 (d,J=2.33 Hz, 1 H); 7.11 (dd, J=8.45, 2.37 Hz, 1 H); 6.97 (d, J=8.34 Hz, 1H); 4.22 (t, J=5.02 Hz, 2 H); 3.82 (t, J=7.50 Hz, 2 H); 3.76-3.63 (m, 2H); 3.59 (d, J=9.30 Hz, 2 H); 3.16 (s, 3 H); 3.14 (m, 2 H); 3.06 (t,J=5.04 Hz, 2 H); 2.66 (s, 1 H); 1.96-1.76 (m, 4 H). LCMS: RT=7.54 min,M+H+=555

Example 1762-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol176

As shown in FIG. 9,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene106 (160 mg, 0.43 mmol),1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole43 (165 mg, 0.51 mmol), cesium carbonate (279 mg, 0.85 mmol),1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride,dichloromethane (17 mg, 5 mol %) were combined in a reaction vial, theatmosphere evacuated and back-filled with nitrogen. THF (5 mL) and water(1 mL) were added and the reaction mixture heated at 85° C. for 4 h. Thereaction mixture was diluted with ethyl acetate and water, the organiclayer separated, dried (Na2SO4), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient0 to 30% ethyl acetate in cyclohexane) to give2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene45 (134 mg, 64%).

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene45 (134 mg, 0.27 mmol) was dissolved in diethyl ether (5 mL) and treatedwith 1M HCl in diethyl ether (1 mL) then methanol (5 mL). After 30 minthe reaction mixture was concentrated to dryness and the resultantresidue triturated in diethyl ether to give 176 as a pale cream solid(105 mg, 86%). ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1 H); 8.23 (s, 1H); 8.19 (d, J=8.23 Hz, 1 H); 8.03 (s, 1 H); 7.96 (s, 1 H); 7.39 (dd,J=8.24, 1.74 Hz, 1 H); 7.29 (d, J=1.68 Hz, 1 H); 5.46-5.36 (m, 1 H);4.34 (t, 2 H); 4.17 (t, J=5.61 Hz, 2 H); 3.78 (t, J=5.58 Hz, 2 H); 3.13(t, J=4.91 Hz, 2 H); 1.52 (d, J=6.57 Hz, 6 H). 1 Exchangeable proton notobserved. LCMS: RT=10.68 min, M+H+=406

Example 1771-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-1-yl)-2-methyl-propan-2-ol177

A mixture of2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride (100 mg, 0.21 mmol), lithium perchlorate (22 mg, 0.21mmol) and DIPEA (72 L, 0.41 mmol) in THF (3 mL) was treated with2,2-dimethyl-oxirane (183 L, 2.06 mmol) and then water (150 L). Thereaction mixture was stirred at RT for 18 h before being concentrated invacuo. The resultant residue was partitioned between DCM and water, theorganic layer separated and concentrated in vacuo. The resultant residuewas subjected to flash chromatography (SiO2, gradient 40 to 100% ethylacetate in cyclohexane) followed by trituration in a mixture MeOH andwater to give 177 as a white solid (58 mg, 54%). ¹H NMR (400 MHz,DMSO-d): δ 8.44 (s, 1 H); 8.28 (s, 1 H); 7.85 (td, J=8.76, 5.90 Hz, 1H); 7.61 (ddd, J=10.27, 8.88, 2.78 Hz, 1 H); 7.36-7.30 (m, 1 H); 7.22(d, J=2.31 Hz, 1 H); 7.08 (dd, J=8.38, 2.35 Hz, 1 H); 6.89 (d, J=8.34Hz, 1 H); 4.21 (t, J=5.02 Hz, 2 H); 4.06 (s, 1 H); 3.12-3.02 (m, 4 H);2.31-2.19 (m, 5 H); 1.60-1.48 (m, 4 H); 1.15 (s, 6 H). LCMS: RT=7.75min, M+H+=521

Example 1782-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-1-yl)-acetamide178

Following the procedure for 143,2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride was reacted with bromo acetamide. The crude product wassubjected flash chromatography (SiO2, gradient 50 to 100% ethyl acetatein cyclohexane). Pure fractions were combined and concentrated diethylether. The resultant precipitate in vacuo and the resultant residuedissolved in DCM and treated with 4M HCl in dioxane then was collectedby filtration to give 178 as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ9.86 (s, 1 H); 8.48-8.43 (m, 1 H); 8.30 (s, 1 H); 8.05 (s, 1 H); 7.85(td, J=8.75, 5.93 Hz, 1 H); 7.74-7.63 (m, 2 H); 7.41-7.34 (m, 1 H); 7.22(d, J=2.30 Hz, 1 H); 7.10 (dd, J=8.45, 2.35 Hz, 1 H); 6.97 (d, J=8.39Hz, 1 H); 4.22 (t, J=5.00 Hz, 2 H); 3.98 (d, J=4.37 Hz, 2 H); 3.60 (t,J=12.26 Hz, 2 H); 3.24-3.13 (m, 2 H); 3.06 (t, J=4.95 Hz, 2 H);2.69-2.61 (m, 1 H); 1.87 (s, 4 H). LCMS: RT=7.46 min, M+H+=506

Example 1792-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-1-yl)-ethanol179

Following the procedure for 142,2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride was reacted with 2-(2-bromo-ethoxy)-tetrahydro-pyran togive 179 as a white solid. ¹H NMR (400 MHz, DMSO-d): δ 9.86 (s, 1 H);8.44 (s, 1 H); 8.29 (s, 1 H); 7.84 (td, J=8.75, 5.94 Hz, 1 H); 7.72 (td,J=9.64, 2.83 Hz, 1 H); 7.43-7.37 (m, 1 H); 7.21 (d, J=2.28 Hz, 1 H);7.09 (dd, J=8.45, 2.36 Hz, 1 H); 6.96 (d, J=8.40 Hz, 1 H); 5.37 (t,J=4.89 Hz, 1 H); 4.21 (t, J=5.01 Hz, 2 H); 3.83 (d, J=5.48 Hz, 2 H);3.65 (d, J=12.04 Hz, 2 H); 3.23 (m, 2 H); 3.10 (m, 4 H); 2.69-2.60 (m, 1H); 2.01-1.80 (m, 4 H). LCMS: RT=7.55 min, M+H+=493

Example 1801-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol180

Following the procedure as for 182, a solution of8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene194 (7.84 g, 20.95 mmol),2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol(11.15 g, 41.90 mmol) and cesium carbonate (20.47 g, 62.8 mmol) indioxan (380 mL) and water (38 mL) was degassed by evacuation/bubblingargon (×3). 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride,dichloromethane (1.71 g, 2.09 mmol) was added and the reaction mixtureheated at reflux for 2 h. The reaction mixture was diluted with water(250 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic fractions were washed with brine (100 mL), dried (MgSO4), andconcentrated in vacuo to give a dark brown slurry. The slurry wastriturated with hot IPA (˜50 mL), allowed to cool to RT and filtered.The solid was washed with cold IPA (˜30 mL) and dried in vacuo to give180 as an off-white solid (6.6 g, 73%). LS/MS (ESI+): m/z 434 (M+H). 1HNMR (400 MHz, DMSO) δ 8.37 (d, J=8.4, 1H), 8.16 (s, 1H), 7.95 (s, 1H),7.91 (s, 2H), 7.39 (dd, J=8.4, 1.7, 1H), 7.28 (d, J=1.7, 1H), 5.90 (dt,J=13.0, 6.5, 1H), 4.72 (s, 1H), 4.52 (q, J=6.2, 4H), 4.04 (s, 2H), 1.49(d, J=6.6, 6H), 1.10 (s, 6H)

Example 1812-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide181

Following the procedure for 143,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride was reacted with bromo acetamide, the crude product wassubjected to reverse phase HPLC (Gemini C18 column gradient 10 to 90%MeOH in water+0.1% HCO2H) to give 181 as a white solid. ¹H NMR (400 MHz,DMSO-d): δ 8.33 (s, 1 H); 8.21-8.14 (m, 2 H); 8.04 (s, 1 H); 7.21 (dd,J=8.42, 1.92 Hz, 2 H); 7.12-7.02 (m, 2 H); 5.44-5.36 (m, 1 H); 4.32 (t,J=5.05 Hz, 2 H); 3.80-3.61 (m, 3 H); 3.30 (t, J=7.44 Hz, 2 H); 3.16-3.09(m, 4 H); 1.52 (d, J=6.59 Hz, 6 H). LCMS: RT=6.49 min, M+H+=408

Example 1822-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol182

To a 10-mL microwave vial was added9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 (0.210 g, 0.56 mmol) and potassium acetate (0.17 g, 1.68 mmol), MeCN(1 mL) and water (2 mL). The mixture was thoroughly purged with N2. Asolution of1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.271 g, 0.84 mmol) in MeCN (1 mL) was added, followed bytetrakis(triphenylphosphine) palladium (65 mg, 0.056 mmol) and the vialwas sealed immediately. The mixture was irradiated with microwave at150° C. for 20 minutes. Complete conversion was observed by LC/MS (asmall amount of des-THP product was observed). The reaction mixture wasdiluted with EtOAc and water and extracted three times with EtOAc. Theorganic phases were combined, dried with MgSO4 and concentrated. Theresidue was purified using ISCO chromatography using 10% MeOH/EtOAc,which gave 170 mg, 0.35 mmol (62%) a white foaming solid as productwhich was immediately dissolved in DCM (2 mL) and treated with 4 Mhydrogen chloride in 1,4-dioxane (0.35 mL). A white precipitatedeveloped during the addition. The reaction was stirred at roomtemperature for 1 h. The reaction mixture was concentrated to drynessand dissolved in DMF/H₂O. This mixture was purified by rp-HPLC toprovide 105 mg (74% yield) of 182 as a white, partially crystallinesolid. LS/MS (ESI+): m/z 406 (M+H). 1H NMR (400 MHz, DMSO) δ 8.37 (d,J=8.4, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.91 (s, 2H), 7.38 (dd, J=8.4,1.8, 1H), 7.27 (d, J=1.7, 1H), 5.91 (dq, J=13.3, 6.7, 1H), 4.91 (t,J=5.3, 1H), 4.58-4.44 (m, 4H), 4.16 (t, J=5.6, 2H), 3.77 (q, J=5.4, 2H),1.49 (d, J=6.6, 6H)

Example 1831-(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidin-1-yl)-2-methyl-propan-2-ol183

Following the procedure for 177,8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride was reacted with 2,2-dimethyl-oxirane to give 183 as awhite solid. ¹H NMR (400 MHz, DMSO-d): δ 8.45 (s, 1 H); 8.31 (s, 1 H);8.17 (s, 1 H); 7.84 (td, J=8.75, 5.92 Hz, 1 H); 7.66 (ddd, J=10.33,9.02, 2.79 Hz, 1 H); 7.40-7.34 (m, 1 H); 7.31 (d, J=8.17 Hz, 1 H); 7.00(d, J=1.69 Hz, 1 H); 6.93 (dd, J=8.25, 1.78 Hz, 1 H); 4.26 (t, J=5.06Hz, 2 H); 3.79 (t, J=7.52 Hz, 2 H); 3.64 (t, J=7.75 Hz, 1 H); 3.35 (t, 2H); 3.08 (t, J=5.05 Hz, 2 H); 2.35 (t, 2 H); 1.10 (s, 6 H). LCMS:RT=7.45 min, M+H+=493

Example 184 methyl2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate184

To methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate(1.0 g, 2.7 mmol), 1-isopropyl-1H-1,2,4-triazole (0.30 g, 2.7 mmol), CuI(1.5 g, 8.1 mmol), Pd(OAc)2 (0.061 g, 0.27 mmol), and cesium carbonate(2.2 g, 6.8 mmol) was added DMF (26 mL). The reaction mixture wasallowed to stir and heat at 100° C. for 24 hours in a sealed vial. Thereaction mixture was cooled to room temperature and poured into amixture of ammonium hydroxide/water (1:2) and EtOAc and filtered througha pad of silica. The layers were separated and the aqueous portion wasextracted with EtOAc. The combined organic extracts were washed withammonium hydroxide (1:2), water, brine, dried over MgSO4, andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography on silica gel eluting with EtOAc to provide 184(0.270 g, 28%). 1H NMR (400 MHz, DMSO) δ 8.54 (d, J=8.4, 1H), 7.97 (d,J=35.2, 2H), 7.70 (dd, J=8.4, 1.7, 1H), 7.57 (d, J=1.7, 1H), 5.99-5.70(m, 1H), 4.57 (q, J=5.9, 4H), 3.87 (s, 3H), 1.49 (d, J=6.6, 6H). MS(ESI(+)): m/z 354.1 (M+H).

Alternatively, methyl2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate(370 mg, 1.3 mmol) in dimethoxyethane (3 mL) was treated with1,1-dimethoxy-N,N-dimethylmethanamine (1 mL, 7.5 mmol) and heated to 90°C. for 0.5 h. LC/MS indicated major desired product. After cooling, thereaction was concentrated to give the crude acylamidine and thensuspended in acetic acid (2.3 mL), treated with isopropylhydrazinehydrochloride (0.29 g, 2.5 mmol). The mixture was heated at 75° C. for30 min., cooled to room temperature and concentrated. Purification byISCO using 100% EtOAc gave 184 (0.32 g, 70% yield). 1H NMR (400 MHz,DMSO) δ 8.54 (d, J=8.4, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.70 (dd,J=8.4, 1.7, 1H), 7.57 (d, J=1.7, 1H), 5.85 (dq, J=13.3, 6.6, 1H), 4.57(q, J=6.0, 4H), 3.87 (s, 3H), 1.49 (d, J=6.6, 6H).

Example 185 methyl2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate185

Following the procedure for 184, methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate andtrifluoroethyltriazole (1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole) werereacted. The product precipitated out of EtOAc and was collected byfiltration to provide 185 (393 mg, 40%). 1H NMR (400 MHz, DMSO) δ 8.51(d, J=8.4, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.71 (dd, J=8.4, 1.7, 1H),7.58 (d, J=1.6, 1H), 5.89 (q, J=8.8, 2H), 4.64-4.49 (m, 4H), 3.87 (s,3H). MS (ESI(+)): m/z 394.0 (M+H).

Alternatively, and following the procedure for 184, methyl2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylatewas reacted with 1,1-dimethoxy-N,N-dimethylmethanamine, followed bytreatment of trifluoroethylhydrazine hydrochloride in acetic acid toprovide 185 (65% yield). 1H NMR (400 MHz, DMSO) δ 8.51 (d, J=8.4, 1H),8.15 (s, 1H), 8.10 (s, 1H), 7.71 (dd, J=8.4, 1.7, 1H), 7.58 (d, J=1.6,1H), 5.89 (q, J=8.8, 2H), 4.65-4.45 (m, 5H), 3.87 (s, 3H), 3.58-3.37 (m,7H)

Example 1862-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol186

Following the same procedure as for 182, Suzuki reaction of9-bromo-2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineand1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleafforded 186 as a white crystalline solid in 72% yield after acidicremoval of the THP group. LS/MS (ESI+): m/z 420 (M+H). 1H NMR (400 MHz,DMSO) δ 8.36 (d, J=8.4, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H),7.38 (dd, J=8.4, 1.7, 1H), 7.27 (d, J=1.7, 1H), 5.83 (dt, J=13.2, 6.6,1H), 4.91 (t, J=5.3, 1H), 4.51 (s, 4H), 4.16 (t, J=5.6, 2H), 3.77 (q,J=5.6, 2H), 1.48 (t, J=9.0, 6H)

Example 18710-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine187

To 10-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.5g, 3.8 mmol), 1-isopropyl-1H-1,2,4-triazole (0.40 g, 3.0 mmol), CuI (1.8g, 9.5 mmol), Pd(OAc)2 (0.071 g, 0.32 mmol), and cesium carbonate (2.6g, 7.9 mmol) was added DMF (20 mL). The reaction mixture was allowed tostir and heat at 100° C. for 24 hours in a sealed vial. The reactionmixture was cooled to room temperature, diluted with EtOAc, and filteredthrough celite. The filtrate was concentrated under reduced pressure. Tothe crude residue was added EtOAc and the solid was collected byfiltration. The filtrate was concentrated and the crude material wasdissolved in DMF and purified by reverse phase HPLC to provide 187 (64mg, 5%). 1H NMR (400 MHz, DMSO) δ 8.43 (dd, J=47.5, 31.0, 1H), 7.97 (s,1H), 7.92 (s, 1H), 7.60-7.39 (m, 1H), 7.04 (d, J=8.7, 1H), 5.74 (dt,J=13.2, 6.6, 1H), 4.76-4.33 (m, 4H), 1.49 (d, J=6.6, 6H). MS (ESI(+)):m/z 374.0 (M+H).

Example 188[4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-methanol188

To a stirring mixture of(4-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-4-yl)-methanolhydrochloride 75 (97 mg, 0.1873 mmol) in IMS (3 mL) was added DIPEA (165L, 0.94 mmol) followed by vinyl sulfone (18 ul, 0.206 mmol) at RT, asillustrated in FIG. 16. After 3 h the solvent was removed in vacuo andthe residue was subjected to HPLC (Gemini C6-Phenyl column, gradient 10to 60%, 20 min ramp) to afford 188 (63 mg, 53%). ¹H NMR δ ppm (DMSO-d6):8.42-8.39 (1 H, m), 8.23 (1 H, s), 8.19 (1 H, s), 7.80 (1 H, td, J=8.77,5.87 Hz), 7.53 (1 H, ddd, J=10.34, 8.85, 2.77 Hz), 7.36 (1 H, d, J=2.40Hz), 7.33-7.27 (1 H, m), 7.12 (1 H, dd, J=8.59, 2.48 Hz), 6.85 (1 H, dd,J=8.55, 4.83 Hz), 4.17 (2 H, t, J=5.04 Hz), 3.22-3.14 (6 H, m), 3.02 (2H, t, J=5.09 Hz), 2.98 (3 H, s), 2.02 (2 H, s), 1.72 (4 H, s). 2 Protonsobscured by water peak. LCMS: RT=6.57 min, M+H+=585

Example 1892-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-1-yl)-2-methyl-propan-1-ol189

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride (250 mg, 0.52 mmol) was dissolved in DMF (3 mL) andtreated with cesium carbonate (336 mg, 1.03 mmol) and 2-bromo-2-methylpropionate (333 L, 2.58 mmol) then heated at 80° C. for 20 h. The cooledreaction mixture was diluted with ethyl acetate and washed with waterand then brine, dried (Na2SO4), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient20 to 70% ethyl acetate in cyclohexane) to give2-(4-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-1-yl)-2-methyl-propionicacid methyl ester. The intermediate 2-methyl-propionic acid methyl ester(195 mg, 0.355 mmol) was dissolved in THF (5 mL) and the solution cooledto 0° C. Lithium aluminium hydride (0.533 mL, 1M solution in THF) wasadded dropwise and the reaction mixture stirred at 0° C. for 15 min thenat RT for 90 min. The reaction mixture was cooled to 0° C. and wateradded, the mixture extracted with ethyl acetate and the organic extractwashed with brine, dried (Na2SO4), filtered and then concentrated invacuo. The resultant residue was subjected to reverse phase HPLC (GeminiC6-Phenyl column, gradient 30 to 60% methanol in water+0.1% HCO2H) togive 189 as a white solid (123 mg, 70%). ¹H NMR δ (ppm)(DMSO-d6): 8.40(1 H, s), 8.24 (1 H, s), 8.17 (1 H, s), 7.79 (1 H, td, J=8.76, 5.90 Hz),7.64-7.57 (1 H, m), 7.34-7.28 (1 H, m), 7.18 (1 H, d, J=2.29 Hz), 7.03(1 H, dd, J=8.38, 2.33 Hz), 6.84 (1 H, d, J=8.33 Hz), 4.16 (2 H, t,J=5.02 Hz), 3.35 (2 H, s), 3.14 (3 H, d, J=11.68 Hz), 3.00 (2 H, t,J=5.05 Hz), 2.38-2.23 (3 H, m), 1.63 (2 H, d, J=12.48 Hz), 1.53-1.39 (2H, m), 1.03 (6 H, s). LCMS: RT=7.89 min, M+H+=521

Example 1901-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol190

Following the same procedure as for 182, Suzuki reaction of9-bromo-2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineand2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olprovided 190. LS/MS (ESI+): m/z 448 (M+H). 1H NMR (400 MHz, DMSO) δ 8.36(d, J=8.4, 1H), 8.16 (s, 1H), 7.94 (s, 1H), 7.87 (s, 1H), 7.39 (dd,J=8.4, 1.8, 1H), 7.27 (d, J=1.7, 1H), 5.90-5.70 (m, 1H), 4.72 (s, 1H),4.51 (s, 4H), 4.04 (s, 2H), 2.25 (s, 3H), 1.47 (d, J=6.6, 6H), 1.10 (s,6H)

Example 1912-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(methylsulfonyl)ethyl)azetidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine191

Following the procedure for 152,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (Example 65) was reacted with vinyl sulfone to give 191 asa white solid. ¹H NMR δ (ppm)(CDCl3): 8.44 (1 H, d, J=8.28 Hz), 7.84 (1H, s), 7.60 (1 H, s), 7.05 (1 H, dd, J=8.32, 1.83 Hz), 6.94 (1 H, d,J=1.78 Hz), 5.99-5.89 (1 H, m), 4.48-4.39 (4 H, m), 3.78-3.70 (2 H, m),3.71-3.62 (1 H, m), 3.25-3.18 (2 H, m), 3.04 (3 H, s), 3.02-2.95 (4 H,m), 1.56 (6 H, d, J=6.64 Hz). LCMS: RT=5.58 min, M+H+=457

Example 1922-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)acetamide192

Following the procedure for 143,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (Example 65) was reacted with bromo acetamide. The crudeproduct was subjected to flash chromatography (SiO2, gradient 0 to 10%MeOH in DCM) then trituration in diethyl ether to give 192 as a whitesolid. ¹H NMR δ (ppm)(CDCl3): 8.46 (1 H, d, J=8.28 Hz), 7.84 (1 H, s),7.61 (1 H, s), 7.07 (1 H, dd, J=8.32, 1.84 Hz), 6.95 (1 H, d, J=1.79Hz), 6.89 (1 H, s), 5.99-5.90 (1 H, m), 5.44 (1 H, s), 4.48-4.45 (2 H,m), 4.43-4.40 (2 H, m), 3.86-3.78 (2 H, m), 3.73-3.63 (1 H, m),3.38-3.31 (2 H, m), 3.20 (2 H, s), 1.56 (6 H, d, J=6.64 Hz). LCMS:RT=5.45 min, M+H+=408

Example 193(1-aminocyclopropyl)(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)methanone193

Following the procedure for 127,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (Example 65) was reacted with1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid. The crudeproduct was subjected to reverse phase HPLC (Gemini C18 column, gradient20 to 95% MeOH in H2O+0.1% HCO2H) to give 193 as a white solid. ¹H NMR δ(ppm)(DMSO-d): 8.36 (1 H, d, J=8.28 Hz), 8.09 (1 H, s), 7.88-7.86 (2 H,m), 7.14 (1 H, dd, J=8.35, 1.82 Hz), 7.01 (1 H, d, J=1.78 Hz), 5.88-5.80(1 H, m), 4.50-4.44 (4 H, m), 3.83-3.71 (2 H, m), 1.44 (6 H, d, J=6.60Hz), 1.05 (2 H, d, J=4.13 Hz), 0.67 (2 H, d, J=4.01 Hz). 2 Exchangeableprotons not seen. 4 protons obscured by water peak. LCMS: RT=6.73 min,M+H+=434

Example 1949-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194

9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide(4.93 g, 16.0 mmol) was taken up in1,1-dimethoxy-N,N-dimethylmethanamine (25 mL, 0.18 mol) and1,2-dimethoxyethane (66.5 mL, 0.640 mol). The heterogeneous mixture wasstirred very vigorously and heated at 65° C. for 1 h. LC/MS showedcomplete consumption of starting material at the end of this period. Thereaction mixture was concentrated in vacuo and carried on to thesubsequent reaction with no further purification steps applied. Thecrude product from the previous reaction (5.8 g, 16.0 mmol) wassuspended in glacial acetic acid (53.2 mL) and isopropylhydrazinehydrochloride (4.36 g, 39.4 mmol) was added. The mixture was heated at100° C. for 2 h. The reaction vessel was cooled to room temp and thesolvent was removed in vacuo. The resultant residue was dry loaded ontosilica gel and purified by ISCO chromatography (120 g column, 100%EtOAc). In total, 2.3 g (39% yield) of 194 was isolated over the twosteps. LC/MS (ESI+): m/z 376 (M+H, with halide isotope). 1H NMR (400MHz, DMSO) δ 8.34 (d, J=8.6, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.36 (dd,J=8.7, 2.0, 1H), 7.30 (d, J=2.0, 1H), 5.85 (dt, J=13.3, 6.6, 1H), 4.55(d, J=15.5, 4H), 1.48 (d, J=6.6, 6H)

Alternatively, to a suspension of8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid1-dimethylamino-meth-(Z)-ylideneamide (8.52 g, 23.5 mmol) in acetic acid(50 mL) was added isopropylhydrazine hydrochloride (3.37 g, 30.5 mmol)and the reaction mixture heated at 100° C. for 1 h. The reaction mixturewas allowed to cool to RT and was poured onto water (500 mL) causing theproduct to precipitate as an off-white solid. The product was collectedby filtration, washed with water (−200 mL) and dried in vacuo at 45° C.for 16 h to yield 194 as an off-white solid (7.88 g, 86%). 1H NMR (400MHz, d6-DMSO) 8.43 (1H, d, J=8.6 Hz), 7.97 (1H, s), 7.92 (1H, d, J=0.6Hz), 7.36 (1H, dd, J=8.6, 2.0 Hz), 7.30 (1H, d, J=2.0 Hz), 5.86 (1H,sept, J=6.6 Hz), 4.56-4.52 (4H, m), 1.48 (6H, d, J=6.6 Hz). LCMS:RT=4.69 min, M+H+=374/376. 1H NMR showed product to contain ˜5%8-iodo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene.

Also alternatively:

Step 1: 4-Bromo-2-fluoro-benzimidic acid ethyl ester hydrochloride

A suspension of 4-bromo-2-fluorobenzonitrile (25.0 g, 125 mmol) in IMS(88 mL) at 0-5° C. and treated dropwise with acetyl chloride (71 mL, 1mol) maintaining the temperature below 10° C. The reaction vessel wassealed and the mixture stirred at RT for 18 h before concentrating invacuo. The resultant residue was triturated in diethyl ether to give4-Bromo-2-fluoro-benzimidic acid ethyl ester hydrochloride as a whitesolid (20.3 g, 57%). ¹H NMR δ (ppm)(DMSO-d): 7.93-7.88 (1 H, m),7.85-7.76 (1 H, m), 7.72-7.64 (1 H, m), 4.60 (2 H, q, J=7.02 Hz),1.47-1.38 (3 H, m).

Step 2: 4-Bromo-2-fluoro-benzamidine hydrochloride

A mixture of 4-bromo-2-fluoro-benzimidic acid ethyl ester hydrochloride(20.3 g, 72 mmol) in IMS (250 mL) at 0-5° C. was saturated with NH3(gas), and the flask sealed before allowing to warm to RT and stirringfor 18 h. Solvent was removed in vacuo and the residue triturated indiethyl ether to give 4-Bromo-2-fluoro-benzamidine hydrochloride as awhite solid (18.1 g, 100%). ¹H NMR δ (ppm)(DMSO-d): 9.26 (4 H, s),7.92-7.87 (1 H, m), 7.71-7.62 (2 H, m).

Step 3: 1-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone

To a solution of 1-isopropyl-1H-[1,2,4]triazole (33 g, 300 mmol) in THFat −10° C. was added n-butyllithium (145 mL, 2.5M, 360 mmol) dropwiseover 45 min, and then the mixture stirred at 0° C. for 30 min. DMA (35mL) was added, the mixture allowed to warm to RT and stirred for 1 h.The resultant suspension was treated with saturated aqueous ammoniumchloride (300 mL). The aqueous phase was extracted with ethyl acetateand the combined organic extracts dried (Na2SO4), filtered andconcentrated in vacuo to give1-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone as a pale orange oil(40.1 g, 87%). ¹H NMR δ (ppm)(CDCl3): 7.93 (1 H, s), 5.58-5.46 (1 H, m),2.72 (3 H, d, J=0.78 Hz), 1.49 (6 H, dd, J=6.61, 0.78 Hz).

Step 4: 2-Bromo-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone

To a solution of 1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (10 g,65.3 mmol) in acetic acid (1 mL) and THF (100 mL) was added a solutionof PTT (phenyltrimethylammonium tribromide, 24.5 g, 65.3 mmol) in THF(100 mL) over 20 min. The reaction mixture was heated at 75° C. beforecooling to RT. The resultant mixture was concentrated in vacuo and theproducts partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate solution. The organic layer was separated, dried (Na2SO4),filtered and concentrated in vacuo to give a residue which was subjectedto flash chromatography (SiO2, gradient 0 to 20% ethyl acetate incyclohexane) to give2-Bromo-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone as an oil (5.4g, 36%). ¹H NMR δ (ppm)(CDCl3): 7.98 (1 H, s), 5.53-5.42 (1 H, m), 4.69(2 H, s), 1.52 (6 H, d, J=6.63 Hz).

Step 5:5-[2-(4-Bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole

To a rapidly stirred mixture of 4-bromo-2-fluoro-benzamidinehydrochloride (9.84 g, 38.8 mmol), potassium hydrogen carbonate (15.6 g,154.8 mmol), THF (98 mL) and water (16 mL) at reflux was added asolution of 2-bromo-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (9.0g, 38.8 mmol) in THF (19 mL) over 15 min. The resulting mixture wasstirred for 18 h at reflux before concentrating in vacuo. The resultantresidue was treated with water and the solid formed collected byfiltration, washed (water, then 1:1 diethyl ether: cyclohexane thendiethyl ether) to give5-[2-(4-Bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazoleas a brown solid (10.1 g, 74%). ¹H NMR δ (ppm)(CDCl3): 8.21-8.14 (1 H,m), 7.90 (1 H, s), 7.80 (1 H, s), 7.47-7.38 (2 H, m), 7.26 (1 H, s),5.91 (1 H, br, s), 1.59 (6 H, d, J=6.63 Hz).

A solution of5-[2-(4-bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole(10.0 g, 28.6 mmol) in DMF (100 mL) was treated with ethylene carbonate(5.3 g, 60.1 mmol) and cesium carbonate (13.9 g, 42.5 mmol) and thenheated at 100° C. for 72 h. Further cesium carbonate (9.0 g, 27.5 mmol)and water (0.5 mL) were added and heating continued for 24 h beforeconcentrating the reaction mixture in vacuo. The resultant residue waspartitioned between DCM and water, the organic layer was isolated,washed with water then brine, dried (Na2SO4), filtered and concentratedin vacuo. The resultant residue was subjected to flash chromatography(SiO2, 1% MeOH in DCM) to give 194 as an off-white solid (5.78 g, 58%).¹H NMR δ (ppm)(CDCl3): 8.04 (1 H, s), 7.83 (1 H, s), 7.50-7.38 (3 H, m),5.93-5.84 (1 H, m), 4.07-4.02 (2 H, m), 3.93-3.88 (2 H, m), 1.53-1.46 (6H, m)

Example 1951-(4-(2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol195

Following the procedure in Example 182,9-bromo-2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinewas coupled with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olto give 195. Yield 22%. MS(ESI+): 447.1. 1H NMR (400 MHz, DMSO) δ 8.34(d, J=8.4, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.63 (s, 1H), 7.36 (dd,J=8.4, 1.7, 1H), 7.25 (d, J=1.7, 1H), 7.00 (d, J=0.6, 1H), 5.68-5.57 (m,1H), 4.72 (s, 1H), 4.48 (s, 4H), 4.03 (s, 2H), 2.10 (s, 3H), 2.07 (s,1H), 1.42 (d, J=6.7, 6H), 1.09 (s, 6H).

Example 1962-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide196 Step 1: ethyl2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate

9-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411 (500 mg, 0.001 mol) and ethyl2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate(594 mg, 0.0015 mol) were reacted under palladium catalyzed Suzukicoupling conditions with Pd(dppf)Cl2 and Cs2CO3 water anddimethoxyethane to give ethyl2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoatetogether with the corresponding acid. LC/MS (ESI+): m/z 490 (M+H)

Step 2:2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoicacid 251

(250 mg, 0.5 mmol) was treated with 1 M of lithium hydroxide in water (2mL) and methanol (1 mL). The reaction was stirred at room temperaturefor 12 h. Acidified by 10% aqueous citric acid to pH=5 and extractedwith EtOAc twice. The combined organic layers were washed with brine,dried and concentrated. The resultant2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoicacid 251 was used as is with no further purification steps. LC/MS(ESI+): m/z 462 (M+H). 1H NMR (500 MHz, DMSO) δ 8.44 (s, 1H), 8.36 (d,J=8.4, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J=8.4, 1.7, 1H), 7.35(d, J=1.7, 1H), 5.82 (dt, J=13.1, 6.6, 1H), 4.52 (s, 4H), 2.25 (s, 3H),1.78 (s, 6H), 1.45 (t, J=13.9, 6H)

Step 3

2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoicacid 251 (90 mg, 0.2 mmol) was dissolved in DMF (2 mL) and treated withNH4Cl (40 mg, 0.8 mmol), DIPEA (0.3 mL, 2 mmol) followed byN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU, 100 mg, 0.4 mmol). The mixture was stirred atroom temperature for 2 hours. Saturated sodium bicarbonate was added,and the mixture was extracted with EtOAc. The combined organics weredried over sodium sulfate and concentrated. The crude was purified by10% MeOH/EtOAc following by trituration with minimal EtOAc to provide 74mg (82% yield) of 196. LC/MS (ESI+): m/z 463(M+H). 1H NMR (500 MHz,DMSO) δ 8.44-8.26 (m, 2H), 8.01 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J=8.4,1.8, 1H), 7.35 (d, J=1.7, 1H), 7.15 (s, 1H), 6.79 (s, 1H), 5.82 (dt,J=13.3, 6.6, 1H), 4.52 (s, 4H), 2.25 (s, 3H), 1.75 (s, 6H), 1.47 (d,J=6.6, 6H)

Example 1972-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)-N,N-dimethylethanesulfonamide197

Following the procedure of Example 152,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (Example 65) was reacted withN,N-dimethylethenesulfonamide to give 197 as a white solid. ¹H NMR δ(ppm)(CDCl3): 8.44 (1 H, d, J=8.28 Hz), 7.84 (1 H, d, J=0.67 Hz), 7.61(1 H, s), 7.05 (1 H, dd, J=8.32, 1.83 Hz), 6.95 (1 H, d, J=1.78 Hz),6.00-5.90 (1 H, m), 4.48-4.39 (4 H, m), 3.80-3.72 (2 H, m), 3.72-3.64 (1H, m), 3.27-3.19 (2 H, m), 3.02-2.89 (4 H, m), 2.87 (6 H, s), 1.56 (6 H,d, J=6.63 Hz). LCMS: RT=6.35 min, M+H+=486

Example 1982-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)-N,N-dimethylacetamide198

Following the procedure for 143,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (Example 65) was reacted with2-chloro-N,N-dimethylacetamide, the crude product subjected to flashchromatography (SiO2, gradient 0 to 6% MeOH in DCM) to give 198 as awhite solid. ¹H NMR δ (ppm)(CDCl3): 8.44 (1 H, d, J=8.28 Hz), 7.84 (1 H,d, J=0.71 Hz), 7.60 (1 H, s), 7.10 (1 H, dd, J=8.33, 1.81 Hz), 6.97 (1H, d, J=1.72 Hz), 6.01-5.91 (1 H, m), 4.48-4.39 (4 H, m), 3.99-3.90 (2H, m), 3.86-3.77 (1 H, m), 3.46-3.38 (4 H, m), 3.00 (3 H, s), 2.93 (3 H,s), 1.56 (6 H, d, J=6.63 Hz). LCMS: RT=5.87 min, M+H+=436.

Example 1999-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine199

2-Amino-2-methyl-1-propanol (0.20 g, 2.3 mmol) was dissolved intetrahydrofuran (2.2 mL) and NaH (60% in mineral oil, 0.0942 g) wasadded. The resulting mixture was stirred for 1 h at room temp. To thismixture was added methyl2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate184 (0.40 g, 1.1 mmol) in THF/DMF (1:1, 10 mL). The entire reactionmixture was stirred at ambient temperature overnight. The reaction wasquenched with water and diluted with EtOAc. Extracted, dried over MgSO4,filtered and concentrated. Dissolved in Methylene chloride (10 mL, 200mmol) and cooled to at 0° C. and treated with thionyl chloride (0.314mL, 4.30 mmol) dropwise. Following the addition, the reaction was warmedto room temp and stirred for 3 h. Concentrated in vacuo and purified byreverse phase HPLC to provide 199 (209 mg, 48% yield). LC/MS (ESI+): m/z393 (M+H). 1H NMR (400 MHz, DMSO) δ 8.47 (d, J=8.4, 1H), 7.99 (s, 1H),7.92 (d, J=3.5, 1H), 7.59 (dd, J=8.4, 1.6, 1H), 7.45 (d, J=1.6, 1H),5.85 (dt, J=13.2, 6.6, 1H), 4.55 (dd, J=10.6, 6.4, 4H), 4.12 (s, 2H),1.49 (d, J=6.6, 6H), 1.30 (s, 6H)

Example 200N-isopropyl-2-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)acetamide200

Following the procedure for 143,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (Example 65) was reacted with 2-chloro-N-isopropylacetamide. The crude product was subjected to reverse phase HPLC (GeminiC18 column gradient 0 to 70% MeOH in H2O+0.1% HCO2H) to give 200 as awhite solid. ¹H NMR δ (ppm)(CDCl3): 8.46 (1 H, d, J=8.28 Hz), 7.85 (1 H,s), 7.63 (1 H, s), 7.05 (1 H, dd, J=8.32, 1.82 Hz), 6.94-6.92 (1 H, m),6.00-5.90 (1 H, m), 4.49-4.40 (4 H, m), 4.12-4.02 (1 H, m), 3.88 (2 H,t, J=7.51 Hz), 3.82-3.71 (1 H, m), 3.41 (2 H, t, J=7.23 Hz), 3.23 (2 H,s), 1.56 (6 H, d, J=6.63 Hz), 1.16 (6 H, d, J=6.57 Hz). 1 Exchangeableproton not seen. LCMS: RT=6.8 min, M+H+=450

Example 2012-(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidin-1-yl)-ethanol201

Following the procedure for 142,8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulenehydrochloride was reacted with 2-(2-bromo-ethoxy)-tetrahydro-pyran, thecrude product subjected to reverse phase HPLC (Gemini C18 column,gradient 10 to 90% MeOH in water+0.1% HCO2H) to give 201 as a whitesolid. ¹H NMR (400 MHz, DMSO-d): δ 8.41 (s, 1 H); 8.28 (s, 1 H); 8.16(s, 1 H); 7.80 (td, J=8.75, 5.92 Hz, 1 H); 7.62 (ddd, J=10.34, 9.02,2.81 Hz, 1 H); 7.37-7.31 (m, 1 H); 7.28 (d, J=8.17 Hz, 1 H); 6.95 (d,J=1.73 Hz, 1 H); 6.89 (dd, J=8.25, 1.81 Hz, 1 H); 4.22 (t, J=5.03 Hz, 2H); 3.69 (t, J=7.37 Hz, 2 H); 3.60 (dt, J=15.08, 7.40 Hz, 1 H); 3.39 (t,J=6.62 Hz, 1 H); 3.23 (t, J=7.74 Hz, 2 H); 3.14 (s, 2 H); 3.05 (t,J=5.14 Hz, 2 H); 2.61 (t, J=5.95 Hz, 2 H). LCMS: RT=7.11 min, M+H+=465

Example 2021-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol202

To a microwave vial containing9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(402 mg, 1.07 mmol) was added potassium acetate (316 mg, 3.22 mmol) anddimethyl sulfoxide (8 mL, 100 mmol). The reaction mixture was purgedwith nitrogen thoroughly and bispinacol ester boronate (310 mg, 3.22mmol) was added followed by[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (87.7 mg, 0.107 mmol) and the vial wassealed. The vial was heated in an oil bath for 24 hours. Completeconversion by LCMS. Filtered through celite with 8/2dichlomethane/methanol and concentrated in vacuo. Flashed 0 to 5%methanol/dichloromethane. Concentrated in vacuo to give2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(117 mg, 26% yield)

2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(113 mg, 0.268 mmol), 1-(4-bromo-1H-imidazol-1-yl)-2-methylpropan-2-oland 1-(5-bromo-1H-imidazol-1-yl)-2-methylpropan-2-ol (88.14 mg, 0.40mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II)chloride (21.90mg, 0.027 mmol), 1,2-dimethoxyethane (3.0 mL, 29 mmol), and 1 M Cesiumcarbonate in water (0.54 mL, 0.5 mmol) were mixed in a microwave vialand microwaved at 140° C. for 15 minutes. Complete reaction by LCMS.Filtered through a paper filter followed by a silica plug. Concentratedin vacuo and purified by HPLC to give 202 (13.7 mg, 12% yield)

Alternatively, to a mixture of 224 (300 mg, 0.75 mmol) and Cs2CO3 (733mg, 2.25 mmol) in DMF (15 mL) under nitrogen was added2,2-dimethyl-oxirane (2 mL, 22.4 mmol). The reaction mixture was heatedat 80° C. for 8 h. Cooled to room temperature, the resulting mixture waspoured into water and extracted with EtOAc. Dried organics over sodiumsulfate and purified by pre-TLC (DCM/MeOH=10:1) to give 202 as a whitesolid (75.3 mg, yield: 23%). 1H NMR (DMSO-d6, 400 MHz): δ8.37 (d, J=8.4Hz, 1H), 7.92 (s, 2H), 7.67 (s, 1H), 7.64 (s 1H), 7.53 (dd, J 1=1.6 Hz,J 2=8.4 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 5.94-5.88 (m, 1H), 4.79 (s,1H), 4.54-4.50 (m, 4H), 3.89 (s, 2H), 1.49 (d, J=6.4 Hz, 6H), 1.09 (s,6H). MS: (ESI, m/z)=434 [M+H]+

Example 2033-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one203

10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine187 (0.057 g, 0.15 mmol), 2-fluoropyridin-3-ylboronic acid (0.026 g,0.183 mmol), potassium acetate (0.059 g, 0.609 mmol), andtetrakis(triphenylphosphine)palladium(0) (8.8 mg, 0.007 mmol), DMF (6mL) and water (0.6 mL) were mixed. Nitrogen was bubbled through thereaction mixture for 5 minutes. The reaction mixture was allowed to stirand heat at 105° C. for 24 hours before cooling, diluting with EtOAc,and filtering through a pad of celite. The filtrate was concentratedunder reduced pressure and diluted with EtOAc. The solution was washedsequentially with water, and brine, before drying over MgSO4 andconcentrating under reduced pressure. The crude material was dissolvedin DMF and purified by reverse phase HPLC to provide10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(47 mg, 80%). MS (ESI(+)): m/z 391.1 (M+H)

To a solution of10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.047 g, 0.12 mmol) in DME (2 mL) was added 10% aq HCl (2 mL). Thereaction mixture was allowed to stir and heat at 80° C. for 18 hoursbefore cooling and concentrating under reduced pressure. The crudematerial was dissolved in DMF and purified by reverse phase HPLC toprovide 203 (25 mg, 55%). 1H NMR (400 MHz, DMSO) δ 11.82 (s, 1H), 8.88(d, J=2.3, 1H), 7.92 (d, J=6.7, 2H), 7.67 (ddd, J=9.0, 7.7, 2.2, 2H),7.38 (d, J=4.8, 1H), 7.07 (d, J=8.6, 1H), 6.31 (t, J=6.7, 1H), 5.81 (dt,J=13.2, 6.6, 1H), 4.54 (q, J=5.8, 4H), 1.48 (d, J=6.6, 6H). MS (ESI(+)):m/z 389.1 (M+H)

Example 2049-(1-(2-(3-fluoroazetidin-1-yl)ethylsulfonyl)azetidin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine204

8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride from Example 65 (200 mg, 0.517 mmol) was stirred in DCM (2mL) with triethylamine (145 L, 1.04 mmol) for 1 h before the addition of2-chloroethanesulfonyl chloride (84 mg, 0.52 mmol). After stirring for 1h further triethylamine (73 L, 0.52 mmol) was added and the mixturestirred for 18 h before diluting with DCM and washing with waterfollowed by brine. The resultant solution was concentrated in vacuo togive a brown oil which was used in the subsequent step withoutpurification. A portion of the brown oil (81 mg, 0.18 mmol) was stirredin 3 mL IMS at RT with 3-fluoro-azetidine hydrochloride (22 mg, 0.22mmol) and triethylamine (56 L, 0.4 mmol) for 18 h before beingconcentrated in vacuo. The resultant residue was dissolved in DCM andthe solution washed with water then brine, dried (Na2SO4), filtered andconcentrated in vacuo. The resultant light brown oil was subjected toflash chromatography (SiO2, gradient 0 to 2% MeOH in DCM) to give 204 asa white solid (37 mg, 40%). ¹H NMR δ (ppm)(CDCl3): 8.49 (1 H, d, J=8.30Hz), 7.84 (1 H, d, J=0.64 Hz), 7.62 (1 H, s), 7.12 (1 H, dd, J=8.34,1.88 Hz), 7.00 (1 H, d, J=1.83 Hz), 5.99-5.91 (1 H, m), 5.19-5.13 (0.5H, m), 5.05-4.99 (0.5 H, m), 4.49-4.46 (2 H, m), 4.45-4.41 (2 H, m),4.26 (2 H, t, J=8.24 Hz), 4.06 (2 H, t, J=7.28 Hz), 3.80-3.63 (3 H, m),3.27-3.22 (1 H, m), 3.21-3.16 (1 H, m), 3.06-3.00 (2 H, m), 2.97-2.90 (2H, m), 1.60-1.54 (6 H, m). LCMS: RT=2.94 min, M+H+=516

Example 2052-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)-2-methylpropanamide205

A suspension of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride from Example 65 (0.23 g, 0.6 mmol) in water (2.5 mL) wastreated with sodium cyanide (49.5 mg, 0.6 mmol) followed by acetone (60mg, 0.91 mmol) in water (0.25 mL) and the mixture stirred at RT for 18h. The mixture was extracted four times with DCM and the combinedextracts were dried (Na2SO4), filtered and concentrated in vacuo to give2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile(0.19 g, 76%). LCMS: RT=3.76 min, M+H+=418.

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile(0.17 g, 0.41 mmol) was dissolved in conc. H2SO4, (2 mL) and the mixtureallowed to stand at room temperature for 3.25 hr before adding to ice.The resultant solution was basified with Na2CO3, further water added,and the mixture extracted with 10% MeOH in DCM. The combined extractswere dried (Na2SO4), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0 to 10%MeOH in DCM) to give 205 as a white solid (97 mg, 54%). ¹H NMR δ(ppm)(CDCl3): 8.46 (1 H, d, J=8.29 Hz), 7.84 (1 H, s), 7.61 (1 H, s),7.13 (1 H, s), 7.08 (1 H, d, J=8.39 Hz), 6.95 (1 H, s), 6.01-5.91 (1 H,m), 5.27 (1 H, s), 4.50-4.40 (4 H, m), 3.62 (3 H, s), 3.33 (2 H, s),1.56 (6 H, d, J=6.63 Hz), 1.23 (6 H, s). LCMS: RT=2.53 min, M+H+=436

Example 2062-(4-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol206

Following the procedure for 184,9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine and1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole were reacted to give9-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.109 g, 10%). 1H NMR (400 MHz, DMSO) δ 8.28 (t, J=21.9, 1H), 8.11 (t,J=7.9, 2H), 7.51-7.35 (m, 1H), 7.32 (d, J=2.0, 1H), 5.88 (q, J=8.8, 2H),4.76-4.29 (m, 4H). MS (ESI(+)): m/z 413.9 (M+H).

Following the procedure for 182,9-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineand1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere reacted to give 206 (0.056 g, 48%). 1H NMR (400 MHz, DMSO) δ 8.33(d, J=8.4, 1H), 8.24 (s, 1H), 8.07 (d, J=11.7, 2H), 7.95 (d, J=8.9, 1H),7.41 (dd, J=8.4, 1.7, 1H), 7.28 (d, J=1.7, 1H), 5.91 (q, J=8.8, 2H),4.91 (t, J=5.3, 1H), 4.54 (dd, J=10.8, 5.6, 4H), 4.16 (t, J=5.6, 2H),3.87-3.69 (m, 2H). MS (ESI(+)): m/z 446.1 (M+H)

Example 2072-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)ethanol207

Tetrakis(triphenylphosphine)palladium(0) (84.0 mg 0.0727 mmol) was addedlast to a degassed solution of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(272 mg, 0.727 mmol) and regioisomers1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazoleand1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazole(600 mg, 1 mmol) in acetonitrile (5 mL, 100 mmol). The reaction washeated in the CEM microwave at 140° C. for 30 minutes with completeconversion by LCMS. Concentrated in vacuo and flash purified 0 to 100%methanol/dichloromethane. The product tubes were concentrated in vacuoto give 270 mg of the regioisomers2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineand2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine.These inseparable compounds were dissolved in 4 N HCl in dioxane (10 mL)and the solution was stirred for 30 minutes at room temperature.Complete deprotection was confirmed by LCMS to give the final compoundswhich were purified by SFC to separate the regioisomer 207 (159.8 mg,54% yield, M+1 406.1)

Alternatively, to a mixture of 224 (300 mg, 0.75 mmol) and Cs2CO3 (733mg, 2.25 mmol) in DMF (15 mL) under nitrogen was added2-(2-bromo-ethoxy)-tetrahydro-pyran (0.68 mL, 4.52 mmol). The reactionmixture was heated at 80° C. for 5 h. Cooled to room temperature, theresulting mixture was poured into water and extracted with EtOAc. Driedorganics over sodium sulfate and purified by pre-TLC (DCM/MeOH=10:1) togive2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineas a yellow oil (250 mg, yield: 68%). LCMS: (ESI, m/z)=490 [M+H]+

To a solution of2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(250 mg, 0.51 mmol) in EtOH (15 mL) was added a solution of hydrogenchloride in dioxane (1.28 mL, 5.1 mmol). The mixture was refluxed for 2h, cooled to room temperature and concentrated. The resultingprecipitates were washed with EtOAc to give 207 as a yellow solid (115.2mg, yield 56%). 1H NMR (Methane-d4, 400 MHz): δ9.12 (d, J=1.2 Hz, 1H),8.78 (s, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.28 (s, 1H), 8.17 (d, J=1.2 Hz,1H), 7.58-7.53 (m, 2H), 5.85-5.78 (m, 1H), 4.71-4.63 (m, 4H), 4.41 (t,J=5.2 Hz, 2H), 3.96 (t, J=5.2 Hz, 2H), 1.66 (d, J=6.8 Hz, 6H). MS: (ESI,m/z)=406 [M+H]+

Example 2082-(5-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)ethanol208

Tetrakis(triphenylphosphine)palladium(0) (84.0 mg 0.0727 mmol) was addedlast to a degassed solution of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(272 mg, 0.727 mmol) and regioisomers1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazoleand1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazole(600 mg, 1 mmol) in acetonitrile (5 mL, 100 mmol). The reaction washeated in the CEM microwave at 140° C. for 30 minutes with completeconversion by LCMS. Concentrated in vacuo and flash purified 0 to 100%methanol/dichloromethane. The product tubes were concentrated in vacuoto give 270 mg of the regioisomers2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineand2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine.These inseparable compounds were dissolved in 4 N HCl in dioxane (10 mL)and the solution was stirred for 30 minutes at room temperature.Complete deprotection was confirmed by LCMS to give the final compoundswhich were purified by SFC to separate the regioisomer 208 (27 mg, 9%yield, M+1 406.1)

Example 2092-(1-(2-morpholinoethyl)-1H-imidazol-2-yl)-10-(1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine209

9-Bromo-2-(1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinewas alkylated with 4-(2-chloroethyl)morpholine to give9-bromo-2-[1-(2-morpholinoethyl)-1H-imidazol-2-yl]-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(yield 51%. MS: 444.2) which was coupled under Suzuki palladium couplingconditions of Example 182 with tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateto give 209. Yield 24%. MS: 432.1. 1H NMR (400 MHz, DMSO) δ 12.95 (s,1H), 8.56 (d, J=2.3, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.51(dd, J=8.4, 2.3, 1H), 7.21 (d, J=1.0, 1H), 7.04 (d, J=8.4, 1H), 6.89 (d,J=1.0, 1H), 4.72 (t, J=7.1, 2H), 4.50 (q, J=5.6, 4H), 3.48-3.40 (m, 4H),2.73 (t, J=7.1, 2H), 2.46-2.36 (m, 4H)

Example 2102-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine210

Similarly to as described in General Procedure C,8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted with4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine.Purification of the crude reaction mixture by reverse phase HPLC gave210. LCMS: 489.2

Example 2112-(4-(2-(3-amino-1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol211

To a microwave vial was added5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine(0.180 g, 0.000462 mol) and potassium carbonate (0.1917 g, 0.001387 mol)in acetonitrile (2.0 mL, 0.038 mol) and water (2.0 mL, 0.11 mol). Thereaction was thoroughly degassed and purged with N2 for 5 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.05344 g, 4.624E-5 mol) andAcetic acid2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethylester (0.1554 g, 0.0005549 mol) were added and the vial was sealedimmediately. The reaction was heated to 140° C. for 20 minutes in themicrowave. The mixture was diluted with methylene chloride and filteredthrough celite. Saturated NH4Cl was added and the mixture was extracted3 times with methylene chloride. The organic layers were combined, driedwith MgSO4 and concentrated. The crude was purified by reverse-phaseHPLC to give 211 (34.6 mg) as a colorless solid. MS (ESI+) 421.1. 1H NMR(400 MHz, DMSO) δ 8.35 (d, J=8.4, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.73(s, 1H), 7.38 (dd, J=8.4, 1.8, 1H), 7.27 (d, J=1.7, 1H), 5.84-5.69 (m,1H), 5.19 (s, 2H), 4.93 (t, J=5.3, 1H), 4.50 (s, 4H), 4.16 (t, J=5.6,2H), 3.77 (q, J=5.6, 2H), 1.42 (d, J=6.6, 6H)

Example 2122-(3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-1-yl)-N-methylacetamide212

A solution of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride from Example 65 (70 mg, 0.2 mmol) in NMP (2 mL) wastreated with sodium phosphate tribasic (85 mg, 0.6 mmol) thenN-methyl-2-chloro acetamide (24 mg, 0.22 mmol) in NMP (0.2 mL) and themixture stirred at RT for 18 h. The mixture was loaded onto an Isolute®SCX-2 cartridge eluting with MeOH then 2M NH3 in MeOH. Appropriatefractions were combined and concentrated in vacuo, the resultant residuewas subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH inDCM) to give 212 (24 mg, 29%). ¹H NMR δ (ppm)(CDCl3): 8.50 (1 H, d,J=8.29 Hz), 7.89 (1 H, s), 7.68 (1 H, s), 7.22 (1 H, s), 7.10 (1 H, dd,J=8.33, 1.81 Hz), 6.99-6.96 (1H, m), 6.03-5.94 (1 H, m), 4.53-4.49 (2 H,m), 4.48-4.44 (2 H, m), 3.96 (2 H, t, J=7.77 Hz), 3.81 (1 H, t, J=7.74Hz), 3.54 (2 H, t, J=7.43 Hz), 3.35 (2 H, s), 2.86 (3 H, d, J=4.93 Hz),1.60 (6 H, d, J=6.63 Hz). LCMS: RT=2.53 min, M+H+=422

Example 2131-(4-(2-(3-amino-1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol213

To a microwave vial was added5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine(0.180 g, 0.000462 mol) and potassium acetate (0.1362 g, 0.001387 mol)in acetonitrile (2.0 mL, 0.038 mol) and water (2.0 mL, 0.11 mol). Thereaction was thoroughly degassed and purged with N2 for 5 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.05344 g, 4.624E-5 mol) and2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol(0.1477 g, 0.0005549 mol) were added and the vial was sealedimmediately. The reaction was heated to 140° C. for 20 minutes in themicrowave. The mixture was diluted with methylene chloride and filteredthrough celite. Saturated NH4Cl was added and the mixture was extracted3 times with methylene chloride. The organic layers were combined, driedwith MgSO4 and concentrated. The crude was purified by reverse-phaseHPLC to give 213 (68.2 mg) as a colorless solid. MS(ESI+) 449.2. 1H NMR(400 MHz, DMSO) δ 8.35 (d, J=8.4, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.73(s, 1H), 7.38 (dd, J=8.4, 1.7, 1H), 7.27 (d, J=1.7, 1H), 5.82-5.68 (m,1H), 5.19 (s, 2H), 4.74 (s, 1H), 4.50 (br, 4H), 4.04 (s, 2H), 1.42 (d,J=6.6, 6H), 1.09 (s, 6H)

Example 2141-(4-(2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol214

9-bromo-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(157 mg, 0.421 mmol),2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol(139.9 mg, 0.5258 mmol), and Tetrakis(triphenylphosphine)palladium(0)(68.05 mg, 0.05889 mmol) dissolved in Acetonitrile (2.66 mL, 50.9 mmol)and with dissolved 2.00 M of Potassium carbonate in Water (0.421 mL).The reaction mixture was degassed. The reaction was microwaved on 150watts, 140° C. for 10 minutes. The reaction was cooled to r.t.,extracted with ethyl acetate to give crude product purified by rHPLC togive 214. MS: (ESI+)=433.2. 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.4 Hz,1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.68 (s, 1H), 7.42-7.31 (m, 2H), 7.26(d, J=1.7 Hz, 1H), 6.94 (s, 1H), 5.66 (dt, J=13.5, 6.7 Hz, 1H), 4.74 (s,1H), 4.50 (s, 4H), 4.03 (s, 2H), 1.46 (d, J=6.7 Hz, 6H), 1.09 (s, 6H)

Example 2152-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide215 Step 1: methyl2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate

Following the procedures as Example 182,9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 and2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanamidewere coupled under Suzuki conditions to give methyl2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate(plus the corresponding acid) in 62% yield. LS/MS (ESI+): m/z 388 (M+H)

Step 2

The mixture of methyl2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoateand corresponding acid (100 mg, 0.22 mmol) was treated with 1 M oflithium hydroxide in water (2 mL) and methanol (0.37 mL). The reactionwas stirred at room temp for 12 h. Acidified by 10% aqueous citric acidto pH=5 and extracted with EtOAc twice. The combined organic layers werewashed with brine, dried and concentrated to give2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoicacid 216. 1H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 8.39 (s, 0H), 8.37 (s,1H), 7.98 (s, 1H), 7.92 (s, 2H), 7.45 (dd, J=8.4, 1.8, 1H), 7.36 (d,J=1.7, 1H), 5.90 (dt, J=13.2, 6.6, 1H), 4.53 (q, J=6.0, 4H), 1.72 (d,J=42.8, 6H), 1.50 (d, J=6.6, 6H).

Step 3

2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoicacid (100 mg, 0.22 mmol) was dissolved in DMF (1 mL) and treatedsequentially with N,N-diisopropylethylamine (0.3 mL, 2.0 mmol), ammoniumchloride (50 mg, 0.9 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU, 200 mg, 0.6 mmol). The resulting mixture wasstirred at room temp for an overnight period. Saturated sodiumbicarbonate was added, and the mixture was extracted with EtOAc. Thecombined organics were dried over sodium sulfate, concentrated, andpurified by rp-HPLC to provide 53 mg (54% yield) of 215. LC/MS (ESI+):m/z 447 (M+H). 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.39 (s, 0H), 8.37(s, 1H), 8.02 (s, 1H), 7.46 (dd, J=8.4, 1.7, 1H), 7.35 (t, J=7.2, 1H),7.20 (s, 1H), 6.85 (s, 1H), 5.90 (hept, J=6.6, 1H), 4.53 (q, J=5.9, 4H),1.74 (s, 6H), 1.50 (d, J=6.6, 6H)

Example 2162-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoicacid 216

9-Bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 and ethyl2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoatewere reacted under Suzuki palladium conditions to give ethyl2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate.LC/MS (ESI+): m/z 476 (M+H)

Ethyl2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoatewas treated with lithium hydroxide in water to give 216. LC/MS (ESI+):m/z 448 (M+H). 1H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 8.38 (d, J=8.4,1H), 7.98 (s, 1H), 7.92 (s, 2H), 7.45 (dd, J=8.4, 1.8, 1H), 7.36 (d,J=1.7, 1H), 5.90 (dt, J=13.2, 6.6, 1H), 4.53 (q, J=6.0, 4H), 1.77 (s,6H), 1.50 (d, J=6.6, 6H)

Example 2172-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine217

Following the same procedure as for 182,9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleprovided 217 in 78% yield. LS/MS (ESI+): m/z 362 (M+H). 1H NMR (400 MHz,DMSO) δ 13.02 (s, 1H), 8.37 (d, J=8.4, 1H), 8.29 (s, 1H), 8.00 (s, 1H),7.54-7.38 (m, 1H), 7.30 (t, J=12.5, 1H), 5.91 (dt, J=13.2, 6.6, 1H),4.57-4.46 (m, 4H), 1.50 (d, J=6.6, 6H)

Example 2183-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one218

Step 1

Following the procedure for 187,10-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine andtrifluoroethyltriazole (1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole) werereacted. The crude mixture was purified by column chromatography onsilica gel eluting with EtOAc prior to concentrating under reducedpressure, dissolving in DMF, and purifying by reverse phase HPLC toprovide10-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.027 g, 2%). 1H NMR (400 MHz, DMSO) δ 8.48 (d, J=2.6, 1H), 8.10 (d,J=5.5, 2H), 7.49 (dd, J=8.7, 2.6, 1H), 7.04 (t, J=7.5, 1H), 5.86 (q,J=8.8, 2H), 4.54 (dt, J=7.4, 3.7, 4H). MS (ESI(+)): m/z 413.9 (M+H)

Step 2

Following the procedure for 203,10-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinewas reacted with 2-fluoropyridin-3-ylboronic acid to give10-(2-fluoropyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.108 g, 55%), 1H NMR (400 MHz, DMSO) δ 8.71 (t, J=2.0, 1H), 8.57-7.83(m, 4H), 7.80-7.39 (m, 2H), 7.22 (d, J=8.5, 1H), 5.88 (q, J=8.8, 2H),4.79-4.38 (m, 4H). MS (ESI(+)): m/z 431.1 (M+H), which was hydrolyzedwith HCl to give 218 (0.072 g, 72%). 1H NMR (400 MHz, DMSO) δ 11.85 (s,1H), 8.78 (d, J=2.3, 1H), 8.09 (d, J=2.8, 2H), 7.69 (ddd, J=8.9, 7.7,2.2, 2H), 7.36 (t, J=23.8, 1H), 7.08 (d, J=8.6, 1H), 6.30 (t, J=6.7,1H), 5.91 (q, J=8.8, 2H), 4.56 (dd, J=13.5, 5.5, 4H). MS (ESI(+)): m/z429.1 (M+H)

Example 2195-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyridin-2-amine219

Following the same procedure as for 182,9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineprovided 219 in 62% yield. LS/MS (ESI+): m/z 388 (M+H). 1H NMR (400 MHz,DMSO) δ 8.42 (d, J=8.4, 1H), 8.33 (d, J=2.4, 1H), 7.93 (d, J=6.5, 2H),7.77 (dd, J=8.7, 2.5, 1H), 7.41 (dd, J=8.5, 1.9, 1H), 7.26 (d, J=1.8,1H), 6.53 (d, J=8.6, 1H), 6.16 (s, 2H), 5.92 (dt, J=13.2, 6.6, 1H),4.60-4.44 (m, 4H), 1.50 (d, J=6.6, 6H)

Example 2202-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)ethanol220

1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-tributylstannanyl-1H-imidazole(0.690 g, 0.00142 mol) was added to a solution of8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(0.293 g, 0.000755 mol) in acetonitrile (4.5 mL, 0.086 mol). The mixturewas thoroughly degassed with nitrogen andtetrakis(triphenylphosphine)palladium(0) (0.0872 g, 0.0000755 mol) wasadded. The vial was sealed and heated in the microwave to 140° C. for 30minutes. Methylene chloride and water were added and the mixture wasfiltered through celite. The aqueous phase was extracted 3× withmethylene chloride. The organic phases were combined, dried with MgSO4and concentrated.

The crude was redissolved in methylene chloride (8.0 mL, 0.12 mol).Hydrogen chloride (4N in dioxane, 0.47 mL, 0.00189 mol) was addeddropwise and the reaction was stirred at room temperature for 1 h. Thereaction was concentrated in vacuo. Methylene chloride and saturatedsodium carbonate were added causing the product to precipitate in theaqueous phase. The aqueous phase was filtered and the solid was purifiedby reverse-phase HPLC to give 220 (42 mg) as a colorless solid. MS(ESI+)420.2

Example 2212-(2-(9-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-imidazol-1-yl)-N-methylacetamide221

Following the procedure for 214,2-(2-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-imidazol-1-yl)-N-methylacetamideand2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olwere reacted under Suzuki conditions to give 221. MS: (ESI+)=462.2. 1HNMR (400 MHz, DMSO) δ 8.38 (d, J=8.4 Hz, 1H), 8.18 (s, 1H), 8.06-7.99(m, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.33 (dd, J=8.4, 1.8 Hz, 1H), 7.26(d, J=1.7 Hz, 1H), 7.11 (d, J=1.1 Hz, 1H), 6.90 (d, J=1.1 Hz, 1H), 5.18(s, 2H), 4.76 (s, 1H), 4.49 (s, 4H), 4.04 (s, 2H), 2.65 (d, J=4.6 Hz,3H), 1.10 (s, 6H).

Example 222N,N-diethyl-2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanamine222

A 5 mL microwave vial was charged with9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(347 mg, 0.928 mmol),N,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine(340 mg, 1.16 mmol), 2 M potassium carbonate in water (0.9 mL, 2 mmol),and acetonitrile (1.52 g, 37.1 mmol) and1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (45.4 mg,0.056 mmol) was added prior to sealing the vial. The reaction was placedon the microwave at 140° C. for 10 minutes. The cooled reaction mixturewas diluted with ethyl acetate and water and partitioned. The organiclayer was washed with brine and, dried over sodium sulfate, concentratedin vacuo and purified by HPLC to give 222 (140 mg, 33% yield, M+1 461.6)

Example 2235-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrimidin-2-amine223

Following the same procedure as for 182,9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amineprovided 223 in 73% yield. LS/MS (ESI+): m/z 389 (M+H). 1H NMR (400 MHz,DMSO) δ 8.66 (s, 1H), 8.45 (d, J=8.4, 1H), 7.93 (d, J=9.7, 2H), 7.46(dd, J=8.5, 1.9, 1H), 7.35 (d, J=1.8, 1H), 6.86 (s, 1H), 5.91 (hept,J=6.4, 1H), 4.61-4.44 (m, 4H), 1.50 (d, J=6.6, 6H)

Example 2249-(1H-imidazol-5-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine224

To a solution of 242 (120 mg, 0.27 mmol) in dioxane (4 mL) was added asolution of hydrochloride in dioxane (0.34 mL, 1.35 mmol). The whole washeated at 60° C. for 2 h, cooled to room temperature and concentrated.To the mixture was added sat. sodium bicarbonate and extracted withEtOAc. Dried organics over sodium sulfate and purified concentratedresidue by pre-TLC (DCM/MeOH=8: 1) to give 224 as a yellow solid (36 mg,yield: 37%). 1H NMR (DMSO-d6, 400 MHz): δ12.29 (s, 1H), 8.37 (d, J=8.4Hz, 1H), 7.91 (s, 2H), 7.75 (s, 1H), 7.69 (s, 1H), 7.55 (d, J=8.0 Hz,1H), 7.45 (s, 1H), 5.94-5.88 (m, 1H), 4.53 (br s, 4H), 1.49 (d, J=6.4Hz, 6H). MS: (ESI, m/z)=362 [M+H]+

Example 2252-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine225

Following the procedure for 152,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt was reacted with vinyl sulfone to give 225 asa white solid. ¹H NMR δ (ppm)(DMSO-d): 8.27 (1 H, d, J=8.29 Hz),7.86-7.84 (2 H, m), 7.00 (1 H, dd, J=8.37, 1.76 Hz), 6.85 (1 H, d,J=1.70 Hz), 5.88-5.78 (1 H, m), 4.44 (4 H, q, J=5.99 Hz), 3.26 (3 H, m),3.00 (3 H, s), 2.95 (2 H, d, J=11.00 Hz), 2.68 (2 H, t, J=6.79 Hz), 2.02(2 H, t, J=11.39 Hz), 1.72 (2 H, d, J=12.62 Hz), 1.57 (2 H, qd, J=12.27,3.58 Hz), 1.42 (6 H, d, J=6.60 Hz). LCMS: RT=2.68 min, M+H+=485

Example 2262-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide226

Following the procedure for 143,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt was reacted with 2-bromo acetamide to give 226as a white solid. ¹H NMR δ (ppm)(DMSO-d): 8.27 (1 H, d, J=8.27 Hz), 7.84(2 H, d, J=2.70 Hz), 7.15 (1 H, s), 7.06 (1 H, s), 7.01 (1 H, d, J=8.43Hz), 6.87 (1 H, s), 5.87-5.78 (1 H, m), 4.44 (4 H, d, J=6.92 Hz),2.90-2.78 (4 H, m), 2.15-2.06 (2 H, m), 1.68 (5 H, s), 1.42 (6 H, d,J=6.59 Hz). LCMS: RT=2.57 min, M+H+=436

Example 2272-hydroxy-1-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropan-1-one227

A solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt (350 mg, 0.71 mmol), 2-hydroxyisobutyric acid(111 mg, 1.07 mmol), EDCI (327 mg, 1.7 mmol, HOBt (230 mg, 1.7 mmol) andDIPEA (0.36 mL, 2.13 mmol) was stirred at RT for 5 h before the additionof saturated aqueous sodium bicarbonate. The resultant mixture wasextracted with DCM (2×30 mL), the combined extracts washed with brinethen dried (MgSO4), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0 to 5%MeOH in DCM) then freeze dried to give 227 as a white solid (141 mg,43%). ¹H NMR δ (ppm)(DMSO-d): 8.31 (1 H, d, J=8.29 Hz), 7.82 (1 H, s),7.78 (1 H, s), 7.03 (1 H, d, J=8.38 Hz), 6.90 (1 H, s), 5.85-5.77 (1 H,m), 4.69 (2 H, d, J=13.25 Hz), 4.48 (4 H, t, J=7.99 Hz), 2.91-2.74 (4 H,m), 1.85 (2 H, d, J=13.04 Hz), 1.63-1.49 (2 H, m), 1.49 (6 H, d, J=6.64Hz), 1.37 (6 H, s). LCMS: RT=3.92 min, M+H+=465

Example 228(2S)-2-hydroxy-1-(3-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one228

8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted under palladium catalyzed, Suzuki conditions with3-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-azetidine-1-carboxylicacid tert-butyl ester to give3-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylicacid tert-butyl ester. MS(ESI+) 531.2.

3-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylicacid tert-butyl ester was reacted with acid to give8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene.MS(ESI+) 431.2.

8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas coupled with DIPEA, HATU, and L-lactic acid to give 228. MS(ESI+)503.2. 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=1.7, 1H), 8.37 (d, J=8.4,1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.42 (dd, J=8.4, 1.7, 1H), 7.32 (d,J=1.7, 1H), 5.92-5.74 (m, 1H), 5.34-5.25 (m, 1H), 5.21 (t, J=5.5, 1H),4.84-4.66 (m, 1H), 4.60-4.53 (m, 1H), 4.52 (s, 4H), 4.40-4.31 (m, 1H),4.26-4.09 (m, 2H), 2.25 (s, 3H), 1.47 (d, J=6.6, 6H), 1.22 (d, J=6.7,3H)

Example 2292-(4-(2-(3-amino-1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)ethanol229

5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylaminewas reacted with1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazoleto give 229 after THP-removal with aqueous HCl purification by reversephase HPLC (49 mg). LCMS: 421.2

Example 2302-(3-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanol230

To a solution of8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenein methylene chloride was added(tert-butyl-dimethyl-silanyloxy)-acetaldehyde and acetic acid followedby sodium triacetoxyborohydride. The reaction was stirred at roomtemperature for about 5 hours and quenched with 1N NaOH. Methylenechloride was added and the mixture was extracted 3 times with methylenechloride. The organic phases were combined, dried with MgSO4 andconcentrated. The mixture was purified by flash chromatography (0-10%MeOH in DCM) to afford8-(1-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-azetidin-3-yl}-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneMS(ESI+) 589.3, which was treated with acid to give 230. 1H NMR (400MHz, DMSO) δ 8.45 (s, 1H), 8.36 (d, J=8.4, 1H), 8.03 (s, 1H), 7.88 (s,1H), 7.41 (d, J=8.3, 1H), 7.32 (d, J=1.6, 1H), 5.90-5.78 (m, 1H), 4.97(quin, J=6.9, 1H), 4.52 (s, 4H), 4.47 (t, J=5.4, 1H), 3.73 (t, J=7.6,2H), 3.47-3.37 (m, 4H), 2.58 (t, J=7.7, 2H), 2.25 (s, 3H), 1.47 (d,J=6.6, 6H)

Example 2315-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine231

5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylaminewas hydrogenated in the presence of 10% Pd on carbon to give 231 afterreverse phase HPLC. LCMS: 311.2.

Example 2322-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine232

A 25-mL round-bottomed flask was charged with9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411 (1.0 g, 2.6 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(bispinacolato bisboronate, 0.719 g, 2.83 mmol), potassium acetate (0.76g, 7.7 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in complexwith dichloromethane (1:1) (0.21 g, 0.26 mmol) under a nitrogenatmosphere. The combined mixture was diluted with dimethylsulfoxide (8.5mL) and heated at 85° C. for 12 h. The reaction mixture was then cooledto room temperature and diluted with water and dichloromethane. Thephases were partitioned and the aqueous portion was extracted thricewith dichloromethane. The organic layers were combined, dried overMgSO4, filtered and concentrated. The residue was purified by flashcolumn chromatography to afford 232 as a protio-dehalogenated by-product(66 mg, 7% yield). MS (ESI+) m/z 310.2 (M+H+), calcd. 310.4. 1H NMR (500MHz, DMSO) δ 8.41 (dd, J=8.0, 1.6 Hz, 1H), 7.89 (s, 1H), 7.33 (dd,J=11.0, 4.3 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H),5.83 (dt, J=13.0, 6.6 Hz, 1H), 4.51 (q, J=5.6 Hz, 4H), 2.26 (s, 3H),1.46 (d, J=6.6 Hz, 6H)

Example 2332-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine233

A mixture of10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine(82.7 mg, 0.250 mmol), palladium on carbon 10% (0.1:0.9,Palladium:carbon black, 83 mg) and triethylamine (0.104 mL, 0.750 mmol)in 5.0 ml of ethanol and 5.0 ml of tetrahydrofuran (5.0 mL, 62 mmol) washydrogenated at 1 atm for 3 hours. The catalyst was filtered out, thefiltrate concentrated, the residue purified by RP HPLC, acetonitriklegradient to give 233. Yield 32 mg (43%). MS(ESI+): 297.2. 1H NMR (500MHz, DMSO) δ 8.40 (s, 1H), 8.30 (d, J=5.2, 1H), 8.25 (d, J=5.2, 1H),8.08 (s, 1H), 7.94 (s, 1H), 5.87 (dt, J=13.0, 6.6, 1H), 4.60 (dd,J=13.1, 5.5, 4H), 1.49 (d, J=6.6, 6H).

Example 2342-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-10-(4-methylpiperazin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine234

A mixture of10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine(132 mg, 0.400 mmol), 1-methyl-piperazine (88.7 uL, 0.800 mmol),palladium acetate (44.9 mg, 0.200 mmol),2,8,9-tri-1-butyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (71.0uL, 0.200 mmol) and Sodium tert-butoxide (38.4 mg, 0.400 mmol) in1,4-Dioxane (8.0 mL) was degassed. The reaction was microwaved on 200watts, 120° C. for 30 minutes. The mixture was filtered and the filtrateconcentrated in vacuum. The residue was partitioned between water andethyl acetate. The organic extracts were washed with water, brine anddried over MgSO4 and concentrated in vacuum. The residue was purified on4 g silica column using 5-10% gradient of methanol containing 1% ofammonia in DCM to give 234. Yield 50 mg (30%). MS: 395.2. 1H NMR (500MHz, DMSO) δ 8.04 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 7.63 (s, 1H),5.69 (dt, J=13.3, 6.6, 1H), 4.61-4.53 (m, 2H), 4.49-4.41 (m, 2H), 3.41(s, 4H), 2.45 (s, 4H), 2.23 (s, 3H), 1.50 (d, J=6.6, 6H).

Example 2352-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine235

8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted under palladium catalyzed, Suzuki conditions with5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine to give 235.MS(ESI+) 388.2. 1H NMR (500 MHz, DMSO) δ 9.24-9.20 (m, 3H), 8.54 (d,J=8.4, 1H), 7.96 (s, 1H), 7.65 (dd, J=8.4, 1.4, 1H), 7.58 (d, J=1.2,1H), 5.96-5.71 (m, 1H), 4.57 (s, 4H), 2.26 (s, 3H), 1.48 (d, J=6.6, 6H)

Example 236945-fluoropyridin-3-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine236

8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted under palladium catalyzed, Suzuki conditions with3-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine togive 236. MS(ESI+) 405.2. 1H NMR (500 MHz, DMSO) δ 8.89 (s, 1H), 8.61(d, J=2.6, 1H), 8.52 (d, J=8.4, 1H), 8.19-8.14 (m, 1H), 7.96 (s, 1H),7.63 (dd, J=8.3, 1.3, 1H), 7.54 (d, J=1.4, 1H), 5.89-5.80 (m, 1H), 4.57(s, 4H), 2.26 (s, 3H), 1.48 (d, J=6.6, 6H)

Example 2372-(3-amino-1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carbonitrile237

5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylaminewas reacted with zinc cyanide to give 237 after reverse phase HPLC.LCMS: 336

Example 238N-(5-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyridin-2-yl)acetamide238

8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted under palladium catalyzed, Suzuki conditions withN-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-acetamideto give 238. MS (ESI+) 444.2. 1H NMR (500 MHz, DMSO) δ 10.63 (s, 1H),8.72 (s, 1H), 8.48 (d, J=8.4, 1H), 8.17 (s, 2H), 7.93 (s, 1H), 7.55 (dd,J=8.4, 1.4, 1H), 7.43 (d, J=1.4, 1H), 5.89-5.80 (m, 1H), 4.55 (s, 4H),2.26 (s, 3H), 2.12 (s, 3H), 1.47 (d, J=6.6, 6H)

Example 2399-Chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine239 Step 1:Methyl-9-chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylate

To methyl1-(2-(2-bromo-5-chlorophenoxy)ethyl)-1H-1,2,4-triazole-3-carboxylate inacetonitrile (10.00 mL, 191.5 mmol) was added cesium carbonate (0.9036g, 2.773 mmol) in a microwave flask with stirbar. The mixture wasdegassed by bubbling nitrogen by syringe. Tetraethylammonium chloride(0.2298 g, 1.387 mmol), palladium acetate (0.1556 g, 0.6933 mmol), andcopper(I) iodide (0.02641 g, 0.1387 mmol;) were added, respectively, andthe vessel was sealed by crimping. Next, the flask was heated whilestirring to 165° C. for 18 min in the microwave. Once the reaction wascooled to room temperature, the crude was filtered through celite,concentrated, and purified by silica gel chromatography, to giveMethyl-9-chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylatein 15% yield. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.6 Hz, 1H), 7.34(dd, J=8.8, 2.7 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.75 (m, 2H), 4.53 (m,2H), 4.05 (s, 3H). LRMS m/z Calcd. for C12H10ClN3O3: 279.04107, found:280.0 [M+1]

Step 2

Methyl-9-chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylate(0.144 g, 0.515 mmol) was dissolved in 3:2:1 THF:MeOH:H2O (5.0 mL), andtreated with 4 N aqueous LiOH (0.644 mL). The mixture was stirred for 30min at 25° C. The reaction was quenched with 1 N aq. HCl (10 mL) and thesolution was extracted with EtOAc (3×20 mL). The combined organicextracts were dried with Na2SO4 and concentrated in vacuo to give9-Chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylicacid (89% yield)

Step 3

To9-Chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylicacid (0.137 g, 0.515 mmol) in N,N-dimethylformamide (1.20 mL, 15.4 mmol)was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.587 g, 1.54 mmol) and6-chloro-1-hydroxybenzotriazole (0.262 g, 1.54 mmol). The mixture wasstirred vigorously, and NH4Cl (0.220 g, 4.12 mmol) was added. After 10minutes, N,N-diisopropylethylamine (0.359 mL, 2.06 mmol) was added. Thereaction was stirred at room temperature for 3 hours. Then, the reactionwas concentrated, taken to dryness, and washed with water. The crudeproduct was purified by a silica gel plug, eluting with DCM/MeOH, andthen by reverse phase HPLC to give9-Chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxamide(5.3% yield)

Step 4

To9-Chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxamide(0.0053 g, 0.020 mmol) in toluene (0.160 mL, 1.50 mmol) was added1,1-dimethoxy-N,N-dimethylmethanamine (0.0150 mL, 0.113 mmol), and themixture was heated in a sealed flask to 102° C. for 2 hours whilestirring. Next, the reaction mixture was cooled and concentrated todryness, and isopropylhydrazine hydrochloride (0.00376 g, 0.0340 mmol)and acetic acid (0.0938 g, 1.56 mmol) were added and the reaction wassealed and heated to 102° C. overnight while stirring. Then, thereaction was concentrated to dryness and taken up in DMF, andpurification by reverse phase HPLC gave 239 in 98% yield. 1H NMR (500MHz, CDCl3) δ 8.56 (d, J=2.6 Hz, 1H), 8.02 (s, 1H), 7.35 (dd, J=8.8, 2.6Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 5.84-5.66 (m, 1H), 4.84-4.70 (m, 2H),4.62-4.47 (m, 2H), 1.61 (s, 6H). LRMS m/z Calcd. for C15H15ClN6O:330.09959, Found: 331.1 [M+1]

Example 2409-bromo-2-(1-isopropyl-3-(methylthio)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine240

1-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-2-methyl-isothiourea(27 mg, 0.068 mmol) was heated with isopropylhydrazine hydrochloride (23mg, 0.20 mmol) in acetic acid (0.9 mL) at 100° C. overnight. The mixturewas concentrated and the crude residue purified by reverse-phase HPLC togive 240. LCMS EI: 422.1

Example 2415-(9-(5-fluoropyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine241

5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylaminewas reacted with3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine werereacted under Suzuki palladium coupling conditions. The crude productwas purified by reverse phase HPLC to give 241. LCMS: 406.2

Example 2422-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine242

1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazolewas prepared by hydrogen with palladium reduction of2-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole.

To a mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine250 mg, 0.67 mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole(204 mg, 0.73 mmol) in dry DMF (2.5 mL) under nitrogen was added CsF(254 mg, 1.68 mmol), CuI (13 mg, 0.067 mmol) and Pd(PPh3)4 (39 mg, 0.034mmol). The reaction mixture was heated at 130° C. for 40 min undermicrowave. Cooled to room temperature, the resulting mixture was pouredinto water and extracted with EtOAc. Dried organics over sodium sulfateand purified by pre-TLC (100% EtOAc) to give 242 as a yellow solid (49.3mg, yield: 17%). 1H NMR (DMSO-d6, 400 MHz): δ8.49 (d, J=8.4 Hz, 1H),8.11 (s, 1H), 7.97 (s, 1H), 7.92 (s 1H), 7.28 (dd, J1=1.6 Hz, J2=8.4 Hz,1H), 7.18 (d, J=6.8 Hz, 2H), 5.92-5.89 (m, 1H), 5.19 (d, J=9.2 Hz, 1H),4.55-4.52 (m, 4H), 4.04 (d, J=11.2 Hz, 1H), 3.60-3.56 (m, 1H), 2.29-1.90(m, 3H), 1.58-1.48 (m, 9H). MS: (ESI, m/z)=446 [M+H]+

Example 2433-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide243

9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411 and ethyl2-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoatewere reacted under Suzuki palladium coupling conditions to give ethyl3-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoateLC/MS (ESI+): m/z 490 (M+H), which was hydrolyzed with lithium hydroxidein water then the corresponding acid was treated with ammonium chloride,HATU, diisopropylethylamine, and DMF to give 243. LC/MS (ESI+): m/z 461(M+H). 1H NMR (500 MHz, DMSO) δ 8.35 (d, J=8.4, 1H), 8.15 (s, 1H), 7.95(s, 1H), 7.86 (s, 1H), 7.36 (dd, J=8.4, 1.7, 2H), 7.25 (d, J=1.7, 1H),6.83 (s, 1H), 5.82 (dt, J=13.2, 6.6, 1H), 4.51 (s, 4H), 4.30 (dd,J=13.5, 7.6, 1H), 4.02 (dd, J=13.5, 7.0, 1H), 2.91 (dd, J=14.3, 7.1,1H), 2.25 (s, 3H), 1.47 (d, J=6.6, 5H), 1.01 (d, J=7.0, 3H)

Example 2442-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(pyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine244

8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted with3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine to give 244.MS(ESI+) 387.2

Example 2455-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-N,N-dimethylpyrimidin-2-amine245

8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted withDimethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amineto give 245. MS(ESI+) 431.2

Example 2465-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-N-methyl-1H-1,2,4-triazol-3-amine246

5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-N-methyl-1H-1,2,4-triazol-3-aminewas hydrogenated in the presence of 10% Pd on carbon to give 246 afterreverse phase HPLC. LCMS: 325.2

Example 247N-isopropyl-2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide247

To a suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt (350 mg, 0.71 mmol) in THF was added potassiumcarbonate (245 mg, 1.78 mmol) followed by N-isopropyl-2-chloroacetamide(106 mg, 0.78 mmol) and the reaction mixture stirred for 18 h at RT thenheated at 50° C. for 2 h. The resultant mixture was concentrated invacuo and the residue subjected to flash chromatography (SiO2, gradient0 to 5% MeOH in DCM to give 247 as a white solid (180 mg, 53%). ¹H NMR δ(ppm)(DMSO-d6): 8.28 (1 H, d, J=8.28 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85(1 H, s), 7.40 (1 H, d, J=8.18 Hz), 7.03 (1 H, dd, J=8.36, 1.77 Hz),6.89 (1 H, d, J=1.72 Hz), 5.88-5.79 (1 H, m), 4.48-4.41 (4 H, m),3.89-3.83 (1 H, m), 2.89-2.79 (4 H, m), 2.13 (2 H, td, J=10.70, 4.11Hz), 1.74-1.64 (4 H, m), 1.43 (6 H, d, J=6.60 Hz), 1.04 (6 H, d, J=6.59Hz). 1 Proton obscured by solvent peak. LCMS: RT=2.94 min, M+H+=478

Example 2482-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,2-dimethylpropanamide248

A biphasic mixture of 50% aqueous sodium hydroxide (2 mL) and DCM (2.5mL) was treated with 2-bromo-2,N-dimethyl-propionamide (121 mg, 0.67mmol), tetrabutylammonium bromide (118 mg, 0.37 mmol) and a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt (300 mg, 0.61 mmol) in DCM (1 mL). Theresultant mixture was stirred at RT for 3 h before the addition offurther tetrabutylammonium bromide (118 mg, 0.37 mmol) and stirring atRT for 18 h. The reaction mixture was diluted with DCM and washed withwater. The combined aqueous extracts were washed with DCM and thecombined organic extracts dried (MgSO4), filtered and concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 0 to 5% MeOH in DCM) followed by trituration in diethylether to give 248 as a cream solid (120 mg, 41%). ¹H NMR δppm)(DMSO-d6): 8.27 (1 H, d, J=8.26 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85(1 H, s), 7.64 (1 H, m), 7.02 (1 H, dd, J=8.34, 1.75 Hz), 6.91 (1 H, d,J=1.70 Hz), 5.88-5.78 (1 H, m), 4.48-4.42 (4 H, m), 2.74 (2 H, d,J=10.86 Hz), 2.59 (3 H, d, J=4.75 Hz), 2.17-2.08 (2 H, m), 1.75-1.69 (4H, m), 1.43 (6 H, d, J=6.60 Hz), 1.05 (6 H, s). 1 Proton obscured bysolvent peak. LCMS: RT=2.78 min, M+H+=478

Example 2492-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylethanesulfonamide249

2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt was reacted with N,N-dimethylethenesulfonamideto give 249 as a white solid. ¹H NMR δ (ppm)(DMSO-d6): 8.28 (1 H, d,J=8.29 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.01 (1 H, dd,J=8.37, 1.77 Hz), 6.85 (1 H, d, J=1.72 Hz), 5.88-5.80 (1 H, m),4.48-4.42 (4 H, m), 3.23-3.15 (2 H, m), 2.95 (2 H, d, J=11.09 Hz), 2.74(6 H, s), 2.68-2.60 (2 H, m), 2.09-1.98 (2 H, m), 1.73 (2 H, d, J=12.61Hz), 1.64-1.55 (2 H, m), 1.43 (6 H, d, J=6.61 Hz). 1 Proton obscured bysolvent peak. LCMS: RT=2.90 M+H+=513

Example 2502-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide250

4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester was prepared from8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(500 mg, 1.12 mmol) and 4-piperidine-1-carboxylic acid tert-butyl esterzinc iodide (1.68 mmol) to give4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (569 mg, 100%). LCMS: RT=4.79 min, M+H+=493.

To a solution of4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (569 mg, 1.16 mmol) in dioxane (15 mL) andmethanol (5 mL) was added 4M HCl in dioxane (15 mL) and the reactionmixture stirred for 20 h at RT before being concentrated in vacuo. Theresultant residue was triturated in a mixture of diethyl ether andmethanol to give2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneHydrochloride as a tan solid (212 mg, 43%). LCMS: RT=2.34/2.66 min,M+H+=393.

A mixture of2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (120 mg, 0.28 mmol) in DMF (1.5 mL) was treated withpotassium carbonate (97 mg, 0.7 mmol) followed by bromo acetamide (43mg, 0.336 mmol) and stirred at RT for 18 h. The reaction mixture wasdiluted with ethyl acetate/methanol and washed with water, the organiclayer dried (Na2SO4), filtered and concentrated in vacuo. The resultantsolid residue was recrystallised from methanol to give 250 as a whitesolid (51 mg, 41%). ¹H NMR δ (ppm)(DMSO-d6): 8.27 (1 H, d, J=8.28 Hz),7.81 (1 H, s), 7.16 (1 H, s), 7.07 (1 H, s), 7.01 (1 H, dd, J=8.36, 1.78Hz), 6.87 (1 H, d, J=1.72 Hz), 5.81-5.73 (1 H, m), 4.45-4.41 (4 H, m),2.89-2.82 (2 H, m), 2.83 (2 H, s), 2.20 (3 H, s), 2.16-2.07 (2 H, m),1.72-1.66 (4 H, m), 1.40 (6 H, d, J=6.61 Hz). 1 Proton obscured bysolvent peak. LCMS: RT=2.97 [M+H]+=450

Example 2512-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoicacid 251

To a solution of 4, 4, 5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5 g, 0.03 mol)and Cesium Carbonate (10 g, 0.03 mol) in DMF (50 mL) was added Ethyl2-bromoisobutyrate (4.2 mL, 0.03 mol). The reaction was heated to 110°C. and stirred overnight. The reaction was cooled to room temperature,diluted with H2O, extracted the aqueous layer with EtOAc (2×) and thecombined organic portions were washed with brine, dried over MgSO4,filtered and concentrated in vacuo. The crude product was a mixture oftwo isomers which was then separated by triturating with hexane toisolate the desired product ethyl2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate.LC/MS (ESI+): m/z 309 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=4.1,1H), 7.84 (s, 1H), 4.22-4.08 (m, 2H), 1.85 (d, J=7.6, 6H), 1.36-1.31 (m,12H), 1.20 (td, J=7.1, 2.8, 3H).

9-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411 and ethyl2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoatewere coupled under Suzuki conditions to give ethyl2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate.LC/MS (ESI+): m/z 490 (M+H)

Ethyl2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate(750 mg, 0.0015 mol) was treated with 1 M of LiOH/H2O (1.6 mL) in MeOH(10 mL). The reaction was allowed to stirred at room temperature for 2hours. The mixture was acidified by 10% citric acid aqueous solution wasuntil PH=5, extracted with EtOAc twice, dried with MgSO4, andconcentrated in vacuo. The crude was purified by Prep HPLC to provide251. LC/MS (ESI+): m/z 462 (M+H). 1H NMR (500 MHz, DMSO) δ 8.44 (s, 1H),8.36 (d, J=8.4, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J=8.4, 1.7,1H), 7.35 (d, J=1.7, 1H), 5.82 (dt, J=13.1, 6.6, 1H), 4.52 (s, 3H), 2.25(s, 2H), 1.78 (s, 4H), 1.45 (t, J=13.9, 4H)

Example 2521-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol252

2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted with 1-(4-Bromo-imidazol-1-yl)-2-methyl-propan-2-ol to give252. MS(ESI+) 448.3

Example 2535-(9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine253

tert-Butyl5-(9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-ylcarbamate(0.200 mg, 0.47 mmol) was dissolved in 1,2-Dichloroethane (3 mL, 40mmol) and trifluoroacetic acid (3 mL, 40 mmol) was added. The reactionmixture was stirred at room temperature for 1.5 hours. Complete reactionwas confirmed by LCMS and the reaction mixture concentrated in vacuo.The crude solid was purified by HPLC to give 253 (18.3 mg, 12% yield)

Example 2542-(4-(2-(3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol254

8-Bromo-2-(5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted with1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazoleunder microwave conditions to give 254. MS(ESI+) 378.2

Example 2552-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-2-methyl-1H-imidazol-1-yl)ethanol255

Compound 256 (90 mg, 0.18 mmol) was dissolved in 3 mL of methanol andHCl-methanol (3 ml, 4M) was added dropwise at 0° C. The mixture wasallowed to warm up to room temperature slowly and stirred at roomtemperature for 2 hours, concentrated. The residue was washed with EtOActo give 65 mg of 255 as HCl salt. Yield=82%. 1H NMR (CDCl3, 400 MHz):δ8.65-8.61 (m, 2 H), 8.17 (s,1 H), 8.00 (s, 1 H), 7.52-7.48 (m, 2 H),5.81-5.78 (m, 1 H), 4.68-4.60 (m, 4 H), 4.31-4.29 (m, 2 H), 3.95-3.92(m, 2 H), 2.74 (s, 3 H), 1.65 (d, J=1.2 Hz, 6H). LC-MS: m/z=404 [M+H+]

Example 2562-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine256

4-Iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazolewas prepared by reaction of 4-iodo-2-methyl-1H-imidazole, Cs2CO3, and2-(2-Bromo-ethoxy)-tetrahydro-pyran in DMF. To a mixture of4-Iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazole(500 mg, 1.9 mmol) in DCM (10 mL) was added ethylmagnesium bromide (0.7ml, 3 mol/L, 2.2 mmol) at −78° C. The temperature of the mixture wasallowed to warm up to about 10° C. slowly and cooled again. Trimethyltinchloride (2.2 ml, 1 mol/1, 2.2 mmol) was added dropwise at −78° C. Afterthe addition, the temperature was allowed to slowly warm up to roomtemperature. The reaction mixture was pouted into saturate NH4Clsolution, then extracted with DCM, The organic was washed with watertwice, dried over anhydrous Na2SO4, concentrated to give 0.44 g of2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethylstannyl)-1H-imidazole. Yield=63%. 1H NMR (CDCl3, 400 MHz): δ 7.04 (s, 1H, ArH), 3.71 (s, 2 H), 2.43 (s, 3 H), 1.24-1.20 (m, 6 H), 0.88 (s, 9H), 0.29 (s, 6 H), 0.06 (s, 9 H). LC-MS: m/z=375 [M+H+]

A mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol),2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethylstannyl)-1H-imidazole(600 mg, 1.6 mmol) in dioxane (2 ml) was bubbled with N2 for about 2 minand then stirred at 120° C. for 35 min under the irradition ofmicrowave. Filtered, concentrated and purified by pre-TLC (EtOAc) togive 130 mg of 256. Yield=32%. 1H NMR (CDCl3, 400 MHz): δ8.44-8.42 (m, 1H, ArH), 7.81 (s, 1 H), 7.58 (s, 1 H), 7.48-7.46 (m, 1 H), 7.42 (d,J=1.6 Hz, 1 H), 7.19 (s, 1 H), 4.51-4.95 (m, 1 H), 4.45-4.44 (t, 1 H),4.39-4.38 (m, 2 H), 4.38-4.37 (m, 2 H), 4.07-4.04 (m, 2 H), 4.00-4.97(m, 1 H), 3.63-3.54 (m, 2 H), 3.40-3.36 (m, 1 H), 2.49 (s, 3 H),1.76-1.60 (m, 4 H),1.48-1.47 (m, 2 H) LC-MS: m/z=504 [M+H+]

Example 2575-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrimidin-2-amine257

8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted with5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine togive 257. MS(ESI+) 403.2

Example 2585-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one258

10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinewas reacted with 6-fluoropyridin-3-ylboronic acid to give10-(6-fluoropyridin-3-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.121 g, 39%). 1H NMR (500 MHz, DMSO) δ 8.67 (d, J=2.4, 1H), 8.52 (d,J=2.6, 1H), 8.25 (td, J=8.2, 2.7, 1H), 7.92 (s, 1H), 7.68 (dd, J=8.5,2.5, 1H), 7.31 (dd, J=8.4, 2.8, 1H), 7.19 (d, J=8.5, 1H), 5.69 (dt,J=13.3, 6.6, 1H), 4.56 (s, 4H), 2.26 (s, 3H), 1.47 (d, J=6.6, 6H). MS(ESI(+)): m/z 405.2 (M+H)

10-(6-Fluoropyridin-3-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinewas hydrolyzed with HCl to give 258 (0.028 g, 25%). 1H NMR (500 MHz,DMSO) δ 11.76 (s, 1H), 8.50 (d, J=2.4, 1H), 7.90 (s, 1H), 7.78 (dd,J=9.5, 2.8, 1H), 7.64 (s, 1H), 7.52 (dd, J=8.5, 2.5, 1H), 7.10 (d,J=8.5, 1H), 6.47 (d, J=9.5, 1H), 5.70 (dt, J=13.2, 6.5, 1H), 4.52 (q,J=5.8, 4H), 2.26 (s, 3H), 1.48 (d, J=6.6, 6H). MS (ESI(+)): m/z 403.2(M+H).

Example 261N-(azetidin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10-amine261

A solution of10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine(90.0 mg, 0.272 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (46.9mg, 0.272 mmol), Palladium Acetate (6.11 mg, 0.0272 mmol), XPhos (13.0mg, 0.0272 mmol), and Sodium-tert-butoxide (52.3 mg, 0.544 mmol) in1,4-Dioxane (1.50 mL, 19.2 mmol) was heated in microwave at 115 C for 20min. The reaction was filtered thru celite then rinsed with EtOAc. Thefiltrate was washed with water and brine. The organic layer was driedNa2SO4, concentrated to give crude intermediate tert-butyl3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10-ylamino)azetidine-1-carboxylatewhich was dissolved in DCM (10.0 mL). Trifluoroacetic Acid (0.419 mL,5.44 mmol) was added and the reaction was stirred 3 h. The reaction wasconcentrated and submitted rHPLC purification to give 261. MS:(ESI+)=367.2. 1H NMR (500 MHz, DMSO) δ 8.29 (s, 1H), 8.23 (s, 1H), 7.98(s, 1H), 7.79 (s, 1H), 5.74 (dt, J=13.1, 6.5 Hz, 2H), 4.73-4.60 (m, 3H),4.58-4.51 (m, 2H), 4.43 (dd, J=12.7, 6.9 Hz, 2H), 4.24 (dt, J=15.9, 5.6Hz, 1H), 2.77 (m, J=34.8, 13.1, 5.3 Hz, 2H), 1.50 (d, J=6.6, 2.9 Hz, 6H)

Example 2623-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10-ylamino)propane-1,2-diol262

A solution of10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine(90.0 mg, 0.272 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine(0.0353 mL, 0.272 mmol), Palladium Acetate (6.11 mg, 0.0272 mmol), XPhos(13.0 mg, 0.0272 mmol), and Sodium-tert-butoxide (52.3 mg, 0.544 mmol)in 1,4-Dioxane (1.50 mL, 19.2 mmol) was heated in microwave at 115° C.for 20 min. The reaction was filtered thru celite then rinsed withEtOAc. The filtrate was washed water, brine. The organic layer was driedNa2SO4, concentrated to give intermediateN-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10-amineto which was added 4.00 M of Hydrogen chloride in dioxane (5.00 mL). Thereaction was stirred 3 h. The reaction was concentrated and submittedHPLC purification to give 262. MS: (ESI+)=386.2. 1H NMR (500 MHz, DMSO)δ 7.99 (s, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.44 (s, 1H), 6.36 (s, 1H),5.86 (dt, J=13.2, 6.6 Hz, 1H), 4.78 (d, J=4.8 Hz, 1H), 4.61-4.46 (m,3H), 4.46-4.33 (m, 2H), 3.64 (dd, J=11.4, 5.3 Hz, 1H), 3.47-3.34 (m,3H), 3.21-3.10 (m, 1H), 1.49 (d, J=6.6 Hz, 6H)

Example 2633-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one263

Following the procedure for 203,10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinewas prepared 0.756 g, 62%. 1H NMR (500 MHz, DMSO) δ 8.73 (s, 1H), 8.24(d, J=4.7, 1H), 8.20-8.10 (m, 1H), 7.91 (s, 1H), 7.60 (d, J=9.4, 1H),7.55-7.45 (m, 1H), 7.20 (d, J=8.5, 1H), 5.70 (dt, J=13.2, 6.6, 1H), 4.57(s, 4H), 2.26 (s, 3H), 1.45 (d, J=6.6, 6H). MS (ESI(+)): m/z 405.2 (M+H)

10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinewas hydrolyzed with HCl to give 263 (0.412 g, 70% yield). 1H NMR (500MHz, DMSO) δ 11.80 (s, 1H), 8.86 (d, J=2.3, 1H), 7.88 (s, 1H), 7.66(ddd, J=9.0, 7.7, 2.2, 2H), 7.37 (d, J=5.0, 1H), 7.06 (d, J=8.5, 1H),6.31 (t, J=6.6, 1H), 5.73 (dt, J=13.2, 6.6, 1H), 4.61-4.47 (m, 4H), 2.25(s, 3H), 1.45 (d, J=6.6, 6H). MS (ESI(+)): m/z 403.2 (M+H).

Example 2651-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-2-methyl-1H-imidazol-1-yl)-2-methylpropan-2-ol265

1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-2-methyl-1H-imidazolewas prepared by reaction of1-(4-iodo-2-methyl-1H-imidazol-1-yl)-2-methylpropan-2-ol, lutidine,tert-butyldimethylsilyl trimethylsulfonate (TBSOTf) in DCM.

To a mixture of1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-2-methyl-1H-imidazole(1.5 g, 3.8 mmol) in DCM (15 mL) was added ethylmagnesium bromide (1.9mL, 3 mol/L, 5.7 mmol) at −78° C. The temperature of the mixture wasallowed to warm up to about 10° C. slowly and cooled again. Trimethyltinchloride (6.5 ml, 1 mol/L, 6.5 mmol) was added dropwise at −78° C. Afterthe addition, the temperature was allowed to slowly warm up to roomtemperature. The reaction mixture was pouted into saturate NH4Clsolution, then extracted with DCM, The organic was washed with watertwice, dried over anhydrous Na2SO4, concentrated to give 0.44 g of1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-4-(trimethylstannyl)-1H-imidazole.Yield=63%. 1H NMR (CDCl3, 400 MHz): δ 7.04 (s, 1 H, ArH), 3.74 (s, 2 H),2.43 (s, 3 H), 1.24-1.20 (m, 6 H), 0.88 (s, 9 H), 0.29 (s, 6 H), 0.03(s, 8 H). LC-MS: m/z=375 [M+H+]

To a mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol),1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-4-(trimethylstannyl)-1H-imidazole(690 mg, 1.6 mmol) in dioxane (2 mL) was bubbled with N2 for about 2 minand then stirred at 120° C. for 35 min under the irradition ofmicrowave. Filtered, concentrated and purified by pre-TLC (pure EtOAc)to give 160 mg of9-(1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-1H-imidazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine.Yield=46%. LC-MS: m/z=548 [M+H+]

9-(1-(2-(tert-Butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-1H-imidazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(110 mg, 0.196 mmol) was dissolved in 5 mL of THF, tetrabutylammoniumfluoride (TBAF, 102 mg, 0.392 mmol) was added at 0° C. The temperaturewas allowed to warm up to room temperature slowly and stirred at roomtemperature for over night. Concentrated, the residue was portioned withEtOAc-water to give 30 mg of 265. Yield=36%. 1H NMR (CDCl3, 400 MHz):δ8.48 (d, J=8.0 Hz, 1 H), 7.87 (s, 1 H), 7.64 (s, 1 H), 7.51-7.47 (m, 2H), 7.26 (s, 1 H), 6.03-5.99 (m, 1 H), 4.51-4.43 (m, 4 H), 3.85 (s, 1H), 2.47 (s, 3 H), 1.65-1.56 (m, 6 H), 1.28-1.26 (m, 6 H). LC-MS:m/z=433 [M+H+]

Example 2693-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10-yl)pyridin-2(1H)-one269

To a solution of10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine(0.087 g, 0.22 mmol) in 1,2-Dimethoxyethane (3.00 mL, 28.9 mmol) wasadded 10% aqueous HCl (3 mL). The reaction was allowed to stir and heatat 80° C. overnight. The reaction was allowed to cool to roomtemperature and concentrated under reduced pressure to give 269,analyzed by rHPLC. MS: (ESI+)=390.2. 1H NMR (500 MHz, DMSO) δ 9.76 (s,1H), 8.45-8.39 (m, 2H), 8.04 (s, 1H), 7.93 (s, 1H), 7.47 (dd, J=6.1, 2.1Hz, 1H), 6.37 (t, J=6.7 Hz, 1H), 5.91 (dt, J=13.3, 6.7 Hz, 2H), 5.91(dt, J=13.3, 6.7 Hz, 1H), 4.61 (dd, J=13.1, 5.5 Hz, 4H), 1.52 (d, J=6.6Hz, 6H).

Example 2702-(5-(9-cyclopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-3-methyl-1H-1,2,4-triazol-1-yl)propan-1-ol270

A microwave vial was charged with a solution of2-[5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-3-methyl-[1,2,4]triazol-1-yl]-propan-1-ol(0.140 g, 0.000346 mol) and Potassium phosphate (0.220 g, 0.00104 mol)in Tetrahydrofuran (2.0 mL) and Water (2.0 mL). The mixture wasthoroughly purged with N2.2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.189 mL, 0.00104mol) and Tetrakis(triphenylphosphine)palladium(0) (0.0400 g, 0.0000346mol) were added and the vial was sealed immediately. The reaction washeated in the microwave to 120° C. for 20 minutes. The reaction wasdiluted with methylene chloride and filtered through celite. SaturatedNH4Cl was added and the mixture was extracted 3 times with methylenechloride. The organic layers were combined, dried with MgSO4 andconcentrated. The crude was purified by reverse-phase HPLC to give 35 mgof 270 as a white solid. MS(ESI+) 366.2. 1H NMR (500 MHz, DMSO) δ 8.26(d, J=8.3 Hz, 1H), 7.82 (s, 1H), 6.86 (dd, J=8.4, 1.7 Hz, 1H), 6.75 (d,J=1.7 Hz, 1H), 5.73-5.57 (m, 1H), 4.85 (t, J=5.4 Hz, 1H), 4.50-4.43 (m,4H), 3.76 (ddd, J=10.7, 7.5, 6.0 Hz, 1H), 3.68-3.62 (m, 1H), 2.24 (s,3H), 1.97-1.85 (m, 1H), 1.39 (d, J=6.7 Hz, 3H), 1.02-0.93 (m, 2H),0.75-0.67 (m, 2H)

Example 2712-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1H-imidazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine271

Following the procedure for 265, a mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineand a mixture of regioisomers2-methyl-1((2-(trimethylsilyl)ethoxy)methyl)-4-(trimethylstannyl)-1H-imidazole and2-methyl-1-(2-(trimethylsilyl)ethoxy)methyl)-5-(trimethylstannyl)-1H-imidazole were reacted to give9-(1-(2-(tert-butyldimethylsilyl)ethoxy)methyl)-2-methyl-1H-imidazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine which was dissolved (360 mg, 0.71mmol) in ethanol (3 mL). To the mixture was added HCl-methanol (3 mL, 4mol/L) dropwise at 0° C. After 30 minutes, the temperature was allowedto warm up to 70° C. and stirred for over night. Concentrated, theresidue was basified with TEA, then purified by per-TLC to give 240 mgof 271. Yield=91%. 1H NMR (MeOD, 400 MHz): δ 8.72 (s, 1 H), 8.60 (d,J=4.4 Hz, 1 H), 8.19 (s, 1 H), 7.87 (s, 1 H), 7.51 (d, J=2.0 Hz, 1 H),7.46 (s, 1 H), 5.72-5.72 (m, 1 H), 4.65-4.64 (m, 2 H), 4.60-4.59 (m, 2H), 2.68 (s, 3 H), 1.63-1.62 (d, J=6.8 Hz, 6 H). LC-MS: m/z=376 [M+H+]

Example 2721-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1-methyl-1H-imidazol-2-yl)-2-methylpropan-2-ol272

To a mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(500 mg, 1.336 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (509 mg,2.004 mmol) in dry DMF (4 mL) under nitrogen was added KOAc (393 mg,4.01 mmol) and Pd(dppf)Cl2 (50 mg, 0.067 mmol). The reaction mixture washeated at 120° C. for 20 min under microwave. Cooled to room temperatureand concentrated, the crude product was purified by columnchromatography (hexanes/EtOAc=3: 1˜1:2) to give2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineasa yellow solid (275 mg, yield: 49%). LCMS: (ESI, m/z)=422 [M+H]+

To a mixture of2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(200 mg, 0.48 mmol) and1-(4-bromo-1-methyl-1H-imidazol-2-yl)-2-methyl-propan-2-ol (166 mg, 0.71mmol) in dry DMF (2 mL) under nitrogen was added CsF (180 mg, 1.19mmol), CuI (9 mg, 0.048 mmol) and Pd(PPh3)4 (27 mg, 0.024 mmol). Thereaction mixture was heated at 130° C. for 40 min under microwave.Cooled to room temperature, the resulting mixture was poured into waterand extracted with EtOAc. Dried organics over sodium sulfate andpurified by pre-HPLC to give 272 as a white solid (34.9 mg, yield: 16%).1H NMR (DMSO-d6, 400 MHz): δ8.51 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H),7.23-7.11 (m, 3H), 5.93-5.89 (m, 1H), 4.54-4.52 (m, 4H), 3.74-3.66 (m,5H), 1.46 (dd, J=6.4 Hz, 6H), 1.24 (brs, 6H). MS: (ESI, m/z)=448 [M+H]+

Example 2731-(4-(2-(3-(hydroxymethyl)-1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol273

Following the procedures as Example 182, Suzuki reaction of(5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)methanoland2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olprovided 273. LCMS: Rt=2.33 min, [M+H]=464

Example 274N-tert-butyl-2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide274

To a suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt (300 mg, 0.61 mmol) in THF (5 mL) was addedpotassium carbonate (295 mg, 2.13 mmol) andN-tert-butyl-2-chloro-acetamide (100 mg, 0.67 mmol). The mixture wasstirred for 5 days before being diluted with DCM and washed with water(2×30 mL). The organic phase was dried (MgSO4) and concentrated invacuo. The resultant residue was triturated in diethyl ether, affording274 as a cream solid (169 mg, 0.34 mmol, 56%). LCMS: RT=3.12 min,[M+H]+=492. ¹H NMR δ (ppm)(DMSO-d): 8.29 (1 H, d, J=8.29 Hz), 7.86 (1 H,d, J=0.63 Hz), 7.85 (1 H, s), 7.15 (1 H, s), 7.03 (1 H, dd, J=8.36, 1.77Hz), 6.89 (1 H, d, J=1.71 Hz), 5.90-5.80 (1 H, m), 4.48-4.41 (4 H, m),2.85 (2 H, d, J=11.24 Hz), 2.81 (2 H, s), 2.20-2.09 (2 H, m), 1.78-1.67(2 H, m), 1.70-1.58 (2 H, m), 1.44 (6 H, d, J=6.60 Hz), 1.25 (9 H, s).1H obscured by solvent.

Example 2752-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N-methylacetamide275

A suspension of8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(1.2 g, 3.09 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.8 g, 5.82 mmol), PdCl2dppf.DCM (339 mg, 0.46mmol) and potassium carbonate (1.9 g, 13.9 mmol) in DMF (10 mL) wasdegassed and then heated at 90° C. under an atmosphere of nitrogen for1.5 h. The cooled reaction mixture was diluted with ethyl acetate andwater, the aqueous extracted with ethyl acetate and combined organicextracts dried (Na2SO4), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient0 to 100% ethyl acetate in cyclohexane, 1% TEA in final eluent) to give4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester as a tan foam (1.5 g, 99%). LCMS: RT=3.77 min,[M+H]+=491

A solution of4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.5 g, 3.06 mmol) in IMS (15 mL) was degassedthen treated with palladium on carbon (10% palladium, 50% water, 450 mg)and the reaction mixture stirred at RT under an atmosphere of hydrogenfor 18 h then at 40° C. for 8 h then RT for 18 h. Further palladium oncarbon was added (10% palladium, 50% water, 450 mg) and stirringcontinued at 40° C. for 8 h before filtering through a pad of Celite®and removal of solvent in vacuo. The resultant residue was dissolved inmethanol (5 mL) and treated with 3M HCl in methanol (10 mL) and stirredat RT for 1.5 h before concentrating in vacuo. The resultant residue wastriturated in diethyl ether to give2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride as a yellow solid (1.26 g, 79%). ¹H NMR 400 MHz (DMSO-d6)δ: 9.03 (2 H, s), 8.37 (1 H, d, J=8.31 Hz), 8.17 (1 H, s), 7.06 (1 H,dd, J=8.37, 1.7 Hz), 6.92 (1 H, d, J=1.7 Hz), 5.78 (1 H, m), 4.54 (4 H,d, J=17.19 Hz), 3.35 (2 H, d, J=12.43 Hz), 2.98 (2 H, m), 2.87 (1 H, m),2.38 (2 H, s), 2.08-1.78 (4 H, m), 1.49 (6 H, d, J=6.57 Hz)

To a suspension of2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (150 mg, 0.35 mmol) was added triethylamine (107 μL, 0.77mmol) followed by 2-chloro-N-methyl-acetamide (41 mg, 0.38 mmol). Theresultant mixture was stirred overnight before the addition oftetrabutylammonium iodide (13 mg, 0.04 mmol) and the reaction stirredfor 24 hours. The mixture was washed with water then extracted with 10%MeOH in DCM (×5).

The combined organic layers were dried (MgSO4), concentrated in vacuoand purified by flash column chromatography (SiO2, gradient 0-10% MeOHin DCM) twice to afford 275 (23 mg, 0.05 mmol, 14%). LCMS: RT=2.63 min,[M+H]+=464. ¹H NMR δ (ppm)(CDCl3): 8.42 (1 H, d, J=8.30 Hz), 7.59 (1 H,s), 7.00 (1 H, dd, J=8.35, 1.83 Hz), 6.88 (1 H, d, J=1.79 Hz), 5.91-5.81(1 H, m), 4.48-4.44 (2 H, m), 4.42-4.36 (2 H, m), 3.13-2.91 (4 H, m),2.85 (3 H, d, J=4.98 Hz), 2.56-2.48 (1 H, m), 2.39 (3 H, s), 2.33 (2 H,s), 1.87 (2 H, s), 1.78 (2 H, s), 1.54 (6 H, d, J=6.65 Hz). NH notobserved.

Alternatively, to a suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt (300 mg, 0.61 mmol) in THF (5 mL) was addedtriethylamine (291 μL, 2.10 mmol) and 2-bromo-N-methyl-acetamide (102mg, 0.67 mmol). The mixture was stirred for 2 hours before the additionof potassium carbonate (169 mg, 1.22 mmol) then for a further 2 hours.The reaction was diluted with DCM and washed with water (2×20 mL), dried(MgSO4) and concentrated in vacuo. The resultant residue was trituratedwith diethyl ether giving 275 as a cream solid (156 mg, 0.35 mmol, 57%).LCMS: RT=2.62 min, [M+H]+=450. ¹H NMR δ (ppm)(DMSO-d6): 8.29 (1 H, d,J=8.27 Hz), 7.86 (1 H, s), 7.85 (1 H, s), 7.66 (1 H, s), 7.02 (1 H, dd,J=8.33, 1.76 Hz), 6.88 (1 H, d, J=1.71 Hz), 5.89-5.79 (1 H, m),4.49-4.42 (4 H, m), 2.88 (2 H, s), 2.84 (2 H, d, J=10.90 Hz), 2.59 (3 H,d, J=4.73 Hz), 2.13 (2 H, s), 1.77-1.67 (4 H, m), 1.44 (6 H, d, J=6.60Hz). 1 H obscured by solvent

Example 276N-ethyl-2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide276

To a suspension of2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (150 mg, 0.35 mmol) in DCM (2 mL) was added triethylamine(107 μL, 0.77 mmol). The resultant mixture was stirred for 10 minutesbefore the addition of 2-chloro-N-ethyl-acetamide (46 mg, 0.38 mmol) andtetrabutylammonium iodide (13 mg, 0.04 mmol). The reaction was stirredat RT for 4 days before the reaction was washed with sodium hydrogencarbonate solution (sat. aq.). The aqueous phase was extracted with 10%MeOH in DCM (×3) and the combined organic layers dried (Na2SO4) thenconcentrated in vacuo. The resultant residue was purified by flashcolumn chromatography (SiO2, gradient 0-10% MeOH in DCM) affording 276(91 mg, 0.19 mmol, 55%). LCMS: RT=2.75 min, [M+H]+=478. ¹H NMR δ(ppm)(CDCl3): 8.43 (1 H, d, J=8.29 Hz), 7.59 (1 H, s), 7.16 (1 H, s),7.00 (1 H, dd, J=8.34, 1.81 Hz), 6.88 (1 H, d, J=1.76 Hz), 5.91-5.80 (1H, m), 4.48-4.44 (2 H, m), 4.42-4.37 (2 H, m), 3.37-3.26 (2 H, m),3.06-2.88 (4 H, m), 2.57-2.47 (1 H, m), 2.38 (3 H, s), 2.30 (2 H, s),1.87 (2 H, d, J=12.74 Hz), 1.76 (2 H, s), 1.54 (6 H, d, J=6.65 Hz), 1.15(3 H, t, J=7.26 Hz).

Example 277N-isopropyl-2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide277

To a suspension of2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (150 mg, 0.35 mmol) in DCM (2 mL) was added triethylamine(107 μL, 0.77 mmol). The resultant mixture was stirred for 10 minutesbefore the addition of 2-chloro-N-isopropyl-acetamide (52 mg, 0.38 mmol)and tetrabutylammonium iodide (13 mg, 0.04 mmol). The reaction wasstirred at RT for 4 days before the reaction was washed with sodiumhydrogen carbonate solution (sat. aq.). The aqueous phase was extractedwith 10% MeOH in DCM (×3) and the combined organic layers dried (Na2SO4)then concentrated in vacuo. The resultant residue was purified by flashcolumn chromatography (SiO2, gradient 0-10% MeOH in DCM) affording 277(88 mg, 0.18 mmol, 51%). LCMS: RT=2.85 min, [M+H]+=492. ¹H NMR δ(ppm)(CDCl3): 8.43 (1 H, d, J=8.29 Hz), 7.59 (1 H, s), 7.01 (1 H, dd,J=8.34, 1.82 Hz), 6.97 (1 H, s), 6.89 (1 H, d, J=1.76 Hz), 5.92-5.82 (1H, m), 4.48-4.44 (2 H, m), 4.42-4.38 (2 H, m), 4.13-4.02 (1 H, m),3.10-2.85 (4 H, m), 2.58-2.46 (1 H, m), 2.38 (3 H, s), 2.35-2.20 (2 H,m), 1.94-1.84 (2 H, s), 1.81-1.68 (2 H, m), 1.54 (6 H, d, J=6.64 Hz),1.16 (6 H, d, J=6.55 Hz)

Example 2782-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide278

To a suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt (300 mg, 0.61 mmol) in THF (5 mL) was addedpotassium carbonate (295 mg, 2.13 mmol) and2-chloro-N,N-dimethyl-acetamide (82 mg, 0.67 mmol). The reaction wasstirred for 4 hours before being diluted with DCM and the mixture washedwith water (2×30 mL), dried (MgSO4) and concentrated in vacuo. Theresultant residue was purified by flash column chromatography (SiO2,gradient 0-5% MeOH in DCM). The resultant material was triturated withdiethyl ether then petroleum ether to give 278 as a white solid (85 mg,0.17 mmol, 29%). LCMS: RT=2.72 min, [M+H]+=464. ¹H NMR δ (ppm)(DMSO-d):8.28 (1 H, d, J=8.29 Hz), 7.86 (1 H, d, J=0.64 Hz), 7.85 (1 H, s), 7.01(1 H, dd, J=8.35, 1.78 Hz), 6.86 (1 H, d, J=1.73 Hz), 5.89-5.79 (1 H,m), 4.48-4.41 (4 H, m), 3.10 (2 H, s), 3.00 (3 H, s), 2.89 (2 H, d,J=10.79 Hz), 2.77 (3 H, s), 2.11 (2 H, dd, J=12.35, 10.20 Hz), 1.71 (2H, d, J=12.52 Hz), 1.61 (2 H, td, J=12.15, 3.73 Hz), 1.44 (6 H, d,J=6.60 Hz). 1H obscured by solvent.

Alternatively, a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulenehydrochloride (66 mg, 0.12 mmol), in DCM (1 mL), methanol (1 mL) and TEA(0.07 mL) was treated with N,N-dimethyl-2-chloroacetamide (17 mg, 0.14mmol) and TBAI (5 mg) and then stirred at RT for 48 h then 30° C. for 18h. The reaction mixture was concentrated in vacuo and the residuepartitioned between DCM and water. The aqueous layer was extracted threetimes with DCM the 10% methanol in DCM, the combined organic extractsdried using a phase separation cartridge before being concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 0 to 10% methanol in DCM) to give 278 as a white solid(34 mg, 61%). LCMS: RT=2.26 min, [M+H]+465. ¹H NMR 400 MHz (DMSO-d6) δ:9.43 (1 H, s), 7.96 (1 H, s), 7.92 (1 H, s), 6.91 (1 H, s), 5.91-5.90 (1H, m), 4.60-4.58 (4 H, m), 3.15 (2 H, s), 3.06 (3 H, s), 2.93 (2 H, d,J=11.06 Hz), 2.82 (3 H, s), 2.63 (1 H, m), 2.15-2.14 (2 H, m), 1.82-1.69(4 H, m), 1.50 (6 H, d, J=6.60 Hz)

Example 2792-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N-methylacetamide279

Following the procedures for Example 278,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulenehydrochloride was reacted with N-dimethyl-2-chloroacetamide to give 279.LCMS: RT=2.62 min, [M+H]+=450

Example 2802-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazepine280 (88)

To amide 87 (0.0485 g, 0.211 mmol) in toluene (1.68 mL, 15.8 mmol) wasadded 1,1-dimethoxy-N,N-dimethylmethanamine (0.158 mL, 1.19 mmol), andthe mixture was heated in a sealed flask to 102° C. for 2 hours whilestirring (FIG. 18). Next, the reaction mixture was cooled andconcentrated to dryness, and isopropylhydrazine hydrochloride (0.0396 g,0.358 mmol) and acetic acid (0.934 mL, 16.4 mmol) were added and thereaction was sealed and heated to 102° C. overnight while stirring.Then, the reaction was concentrated to dryness and taken up in DMF, andpreparative HPLC (acetonitrile/water) gave 280 in 42% yield. 1H NMR (500MHz, CDCl3) δ 8.23 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.30 (dd, J=15.6,7.8 Hz, 2H), 7.23 (d, J=7.4 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H), 5.77-5.69(m, 1H), 4.51 (t, J=5.6 Hz, 2H), 3.56 (t, J=5.6 Hz, 2H), 1.60 (d, J=6.6Hz, 6H). LRMS m/z Calcd. for C12H16N6O: 296.13856, found: 297.1 [M+1].

Example 28110-fluoro-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine281

10-Fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamidefrom Example 90 (0.2 g, 0.81 mmol), dimethylacetamide-dimethyacetal(0.36 mL, 2.4 mmol), and toluene (10 mL, 90 mmol) were combined in around bottom flask with a vigreux condensation column attached. Heatedat 95° C. for more than 24 hours and concentrated in vacuo. The residuewas dissolved in acetic acid and isopropylhydrazine hydrochloride (0.11g, 0.97 mmol) was added and heated at 95° C. with a vigreux condensationcolumn attached for four hours. Complete reaction by LCMS. Concentratedin vacuo and purified by HPLC to give 281 (67.7 mg, 26% yield, M+1328.1)

Example 2829-(1,2-dimethyl-1H-imidazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine282

To a 100 mL round bottom flask charged with NaH (12 mg, 0.5 mmol) wasadded DMF (6 mL) dropwise, followed by 271 (100 mg, 0.25 mmol). Afterstirring for about 1 hour, iodomethane (48 mg, 0.33 mmol) was addeddropwise at 0° C. in THF. Then the mixture was allowed to warm up toroom temperature slowly and stirred for 2 hours. The reaction mixturewas poured into water, extracted with EtOAc, the organic phase was driedover anhydrous Na2SO4, concentrated, then purified by pre-TLC (EtOAc) togive 50 mg (52% Yield) of 282. 1H NMR (CDCl3, 400 MHz): δ8.48 (d, J=8.0Hz, 1 H), 7.87 (s, 1 H), 7.64 (s, 1 H), 7.48-7.44 (m, 2 H), 7.14 (s, 1H), 6.04-5.98 (m, 1 H), 4.51-4.43 (m, 4 H), 3.62 (s, 3 H), 2.45 (s, 3H),1.60 (d, J=6.8 Hz, 6 H), and 15 mg (16% yield) of the regioisomer9-(1,2-dimethyl-1H-imidazol-5-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine291 1H NMR (CDCl3, 400 MHz): δ8.57 (d, J=8.0 Hz, 1 H), 7.87 (s, 1 H),7.87 (s, 1 H), 7.69 (s, 1 H), 7.16 (d, J=6.8 Hz, 1 H), 7.06-7.04 (m, 2H), 6.02-5.96 (m, 1 H), 4.54-4.52 (m, 2 H), 4.48-4.47 (m, 2 H), 3.59 (s,3 H), 2.46 (s, 3 H),1.60 (d, J=6.8 Hz, 6 H). LC-MS: m/z=389 [M+H+].

Example 2852-(4-(2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)ethanol285

8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidamide was reacted with dimethylacetamide-dimethylacetal in toluene,followed by dissolution in acetic acid and treatment withmethylhydrazine hydrochloride to give8-Bromo-2-(2,5-dimethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene.MS(ESI+) 360.0/362.0

To a microwave vial was added8-Bromo-2-(2,5-dimethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(0.150 g, 0.000416 mol) and Potassium acetate (0.123 g, 0.00125 mol) inAcetonitrile (2.0 mL) and Water (2.0 mL). The solution was thoroughlypurged with N2.1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(0.148 g, 0.000458 mol) and Tetrakis(triphenylphosphine)palladium(0)(0.0481 g, 0.0000416 mol) were added and the vial was immediatelysealed. The reaction was heated in the microwave to 140° C. for 20minutes. The mixture was partitioned between saturated NH4Cl andmethylene chloride and extracted 3 times with methylene chloride. Theorganic phases were combined, dried with MgSO4, and concentrated. Thecrude was dissolved in methylene chloride (5.0 mL) and hydrogen chloride(0.00125 mol, 4N in dioxane, 0.31 mL) was added dropwise. The reactionwas stirred at room temperature for 1 hour. The mixture was concentratedand partitioned between saturated sodium bicarbonate and methylenechloride and extracted 3 times with methylene chloride. Most of theproduct precipitated in the aqueous phase—the mixture was filtered andsubmitted to reverse-phase HPLC, then recrystallized in EtOH/MeOH toafford 24 mg 285 as a white solid. MS(ESI+) 392.2. 1H NMR (500 MHz,DMSO) δ 8.40 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.88 (s,1H), 7.36 (dd, J=8.4, 1.7 Hz, 1H), 7.27 (d, J=1.7 Hz, 1H), 4.90 (t,J=5.3 Hz, 1H), 4.54-4.48 (m, 4H), 4.21 (s, 3H), 4.16 (t, J=5.7 Hz, 2H),3.77 (q, J=5.6 Hz, 2H), 2.24 (s, 3H)

Example 2862-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-methoxyethyl)piperidin-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine286

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetic acid salt (300 mg, 0.61 mmol) in DMF (3.5 mL) were addedpotassium carbonate (290 mg, 2.10 mmol) and 1-bromo-2-methoxy-ethane (93mg, 0.67 mmol). The resultant reaction mixture was stirred at 60° C. for4 hours before being cooled to RT and diluted with DCM. The mixture waswashed sequentially with sodium hydrogen carbonate solution (sat. aq.),water and brine then dried (MgSO4) and concentrated in vacuo. Theresultant residue was purified by flash column chromatography (SiO2,gradient 0-8% MeOH in DCM) and triturated with petroleum ether to afford286 as a white solid (127 mg, 0.29 mmol, 48%). LCMS: RT=3.02 min,[M+H]+=437. ¹H NMR δ (ppm)(DMSO-d6): 8.28 (1 H, d, J=8.28 Hz), 7.86 (1H, d, J=0.62 Hz), 7.85 (1 H, s), 7.01 (1 H, dd, J=8.36, 1.77 Hz), 6.85(1 H, d, J=1.72 Hz), 5.90-5.80 (1 H, m), 4.45 (4 H, m), 3.40 (2 H, t,J=5.89 Hz), 3.20 (3 H, s), 2.93 (2 H, d, J=11.11 Hz), 2.01 (2 H, dd,J=12.41, 10.21 Hz), 1.70 (2 H, d, J=12.52 Hz), 1.58 (2 H, ddd, J=24.42,12.21, 3.61 Hz), 1.44 (6 H, d, J=6.60 Hz). 3H obscured by solvent.

Example 2872-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropanamide287

2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile(312 mg, 0.70 mmol) was added concentrated sulfuric acid (3.5 mL). Theresultant mixture was stirred for 3.5 hours at RT before being pouredonto ice and basified with sodium carbonate. The aqueous mixture wasextracted with 10% MeOH in DCM (×5). The combined organic layers weredried (Na2SO4) and concentrated in vacuo. The resultant residue waspurified by flash column chromatography (SiO2, gradient 0-10% MeOH inDCM), then triturated with diethyl ether (x 3), to afford 287 (196 mg,0.42 mmol, 60%). LCMS: RT=2.67 min, [M+H]+=464. ¹H NMR δ (ppm)(DMSO-d):8.27 (1 H, d, J=8.27 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.17(1 H, d, J=3.55 Hz), 7.03 (1 H, dd, J=8.34, 1.74 Hz), 6.91-6.89 (2 H,m), 5.89-5.79 (1 H, m), 4.48-4.41 (4 H, m), 2.80 (2 H, d, J=10.82 Hz),2.17-2.09 (2 H, m), 1.77-1.60 (4 H, m), 1.44 (6 H, d, J=6.60 Hz), 1.05(6 H, s). 1H obscured by solvent.

Example 2882-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)ethanol288

To a suspension of2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (100 mg, 0.23 mmol) in DMF (2 mL) was added sodiumphosphate dibasic (107 mg, 0.75 mmol), triethylamine (2 drops) and2-(2-bromo-ethoxy)-tetrahydro-pyran (38 μL, 0.25 mmol). The resultantmixture was stirred overnight at RT before a further addition oftriethylamine (100 μL) was made. The reaction was stirred at 50° C. for5 hours then allowed to stand at RT over the weekend. The reaction washeated to 50° C. and stirred overnight before the addition of2-(2-bromo-ethoxy)-tetrahydro-pyran (38 μL, 0.25 mmol) and potassiumiodide (10 mg, 0.06 mmol) then stirred overnight at 55° C. The solutionwas cooled and loaded onto a SCX-2 cartridge, washed with MeOH theneluted with 2M NH3 in MeOH. The resultant residue was purified by flashcolumn chromatography (SiO2, gradient 0-10% MeOH in DCM) this gave 288(31 mg, 0.07 mmol, 31%). LCMS: RT=2.59 min, [M+H]+437. ¹H NMR δ(ppm)(CDCl3): 8.42 (1 H, d, J=8.30 Hz), 7.58 (1 H, s), 7.00 (1 H, dd,J=8.34, 1.83 Hz), 6.88 (1 H, d, J=1.78 Hz), 5.93-5.83 (1 H, m),4.46-4.43 (2 H, m), 4.41-4.37 (2 H, m), 3.70 (2 H, t, J=5.19 Hz), 3.17(2 H, d, J=11.24 Hz), 2.68 (2 H, t, J=5.17 Hz), 2.62-2.50 (1 H, m), 2.38(3 H, s), 2.36-2.27 (2 H, m), 2.05-1.85 (4 H, m), 1.54 (6 H, d, J=6.65Hz). OH not observed

Example 2892-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropanamide289

To2-{4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1.3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile(140 mg, 0.31 mmol) was added concentrated sulfuric acid (1.75 mL). Themixture was stirred at RT for 3.5 hours before the reaction was dilutedwith ice and neutralised with sodium carbonate. The aqueous mixture wasextracted with 10% MeOH in DCM (×5) before the organic phase was dried(MgSO4) and concentrated in vacuo. The resultant residue was purified byflash column chromatography (SiO2, gradient 0-10% MeOH in DCM). Thematerial was triturated with diethyl ether before being purified byreverse phase HPLC (C18, gradient 20-70% MeOH/0.1% formic acid inwater/0.1% formic acid). The resultant residue was taken up into MeOH(1.2 mL) and treated with 0.2 M HCl in diethyl ether. The solution wasconcentrated in vacuo affording 289 (14 mg, 0.03 mmol, 9%). LCMS:RT=2.65 min, [M+H]+=478. ¹H NMR δ (ppm)(DMSO-d6): 9.50 (1 H, m), 8.33 (1H, d, J=8.29 Hz), 7.97 (1 H, s), 7.93 (1 H, s), 7.86 (1 H, s), 7.02 (1H, dd, J=8.36, 1.75 Hz), 6.87 (1 H, d, J=1.71 Hz), 5.78-5.71 (1 H, m),4.50-4.44 (4 H, m), 3.19-3.04 (2 H, m), 2.91-2.80 (1 H, m), 2.25 (3 H,s), 2.12 (2 H, d, J=13.49 Hz), 1.98 (2 H, d, J=13.54 Hz), 1.51 (6 H, s),1.43 (6 H, d, J=6.59 Hz). 2H obscured by solvent.

Example 2901-(5-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-imidazol-2-yl)-2-methylpropan-2-ol290 Step 1

To a solution of imidazole (81.6 g, 1.2 mol) in dry THF (2.5 L) wasslowly added NaH (86.4 g, 3.6 mol) in small portions at −78° C. Afterall NaH was added, the mixture was stirred at −78° C. for 30 min, and2-chloro-tetrahydropyran solution, prepared by hydrogen chloride gastreatment of dihydropyran, was added to the reaction mixture dropwise.The mixture was slowly warmed to r.t. and it was stirred at r.t. for 2h. Methanol was added to quench the excess NaH. The mixture wasconcentrated with a rotary evaporator. Water was added and it wasextract with EtOAc (500 mL×3), dried over MgSO4, and purified by neutralAl2O3 column chromatography (petroleum ether 5 L, petroleumether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc). Thelast four fractions were pooled and concentrated to give1-(tetrahydro-pyran-2-yl)-1H-imidazole (140 g, 76%). 1H NMR (CDCl3): δ7.65 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 5.20 (dd, J=2.6, 9.5 Hz, 1H),4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.01-1.89 (m, 3H), 1.69-1.60 (m,3H)

Step 2:2-methyl-1-[1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-propan-2-ol

To the solution of 1-(tetrahydro-pyran-2-yl)-1H-imidazole (7.6 g, 50mmol) in dry THF (500 ml) at −78° C. was added n-BuLi solution (2.5 M inhexanes, 25 mL, 60 mmol, 1.2 equiv). The reaction mixture was slowlywarmed to 0° C. and stirred at 0° C. for 30 min. After it was cooled to−78° C., 2,2-dimethyloxirane (7.2 g, 100 mmol) was added and it wasstirred for 1 h. The reaction mixture was warmed to r.t. slowly andstirred at r.t. overnight. MeOH was added and the reaction mixture wasconcentrated by a rotary evaporator. Water (30 ml) was added and it wasextracted with CH2Cl2 (15 ml×3). The organic layer was dried over MgSO4,concentrated, and purified by neutral Al2O3 column chromatography(CH2Cl2:MeOH=100:1) to give 8 gm of2-methyl-1-[1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-propan-2-ol(75%). 1H NMR (CDCl3): δ 7.04 (s, 1H), 6.95 (s, 1H), 5.13 (dd, J=2.6,9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.82 (d, J=12.0 Hz,2H), 2.01-1.89 (m, 4H), 1.92 (m, 1H), 1.69-1.60 (m, 3H), 1.24 (m, 6H)

Step 3:1-[4-bromo-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-2-methyl-propan-2-ol

To a solution of2-methyl-1-[1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-propan-2-ol(1.12 g, 5 mmol) in DMF (10 mL) at −78° C. was added NBS (0.72 g, 4mmol) in DMF (pre-cooled to −78° C.). The reaction mixture was warmed tor.t. slowly and stirred at r.t. overnight. The solvent was removed undervacuum and purified by neutral Al2O3 column chromatography(CH2Cl2:MeOH=100:1) to give 0.5 gm of1-[4-bromo-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-2-methyl-propan-2-ol(34%). 1H NMR (CDCl3, 400 MHz): δ 7.03 (s, 1H), 5.13 (dd, J=2.6, 9.6 Hz,1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.82 (d, J=12.0 Hz, 2H),2.01-1.89 (m, 4H), 1.92 (m, 1H), 1.69-1.60 (m, 3H), 1.24 (m, 6H)

Step 4:2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

To a mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(500 mg, 1.3 mmol) and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[1,3,2]dioxaborolanyl (509 mg,2.0 mmol) in dry DMF (4 mL) under nitrogen was added KOAc (393 mg, 4.0mmol) and Pd(dppf)Cl2 (50 mg, 0.067 mmol). The reaction mixture washeated at 120° C. for 20 min in a microwave reactor. After it was cooledto room temperature and concentrated, the crude product was purified bycolumn chromatography (hexanes/EtOAc=3:1 to 1:2) to give2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineas a yellow solid (275 mg, 49%). LCMS: (ESI), m/z 422 [M+H]+

Step 5:1-[4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-2-methyl-propan-2-ol

To a mixture of2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(600 mg, 1.42 mmol) and1-(4-bromo-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl)-2-methyl-propan-2-ol(648 mg, 2.1 mmol) in dry DMF (6 mL) under nitrogen was added CsF (534mg, 3.53 mmol), CuI (27 mg, 0.14 mmol) and Pd(PPh3)4 (81 mg, 0.07 mmol).The reaction mixture was heated at 120° C. for 20 min in a microwavereactor. It was filtered, concentrated and purified by columnchromatography (DCM/MeOH=20:1) to give1-[4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-2-methyl-propan-2-olas brown oil (1.1 g). LCMS: (ESI, m/z)=518 [M+H]+.

Step 6

To a solution of1-[4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-2-methyl-propan-2-ol(735 mg, 1.42 mmol) in EtOH (15 mL) was added a solution of hydrogenchloride in MeOH (7.1 mL, 28.4 mmol). The reaction mixture was heated atreflux for 5 h, cooled to r.t. and concentrated. Saturated NaHCO3solution was added slowly and the reaction mixture was extracted withEtOAc. The combined organic layer was dried over Na2SO4, filtered andconcentrated. The crude product was purified by prep-TLC (DCM:MeOH=8:1)to give 290 as a yellow solid (74 mg, 12%). 1H NMR (CDCl3, 400 MHz): δ8.44 (d, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.58 (s, 1H), 7.43-7.36 (m, 2H),7.28 (s, 1H), 5.95-5.91 (m, 1H), 4.45-4.02 (m, 4H), 2.97 (s, 2H), 1.60(d, J=6.8 Hz, 6H), 1.30 (s, 6H). MS: (ESI, m/z)=434 [M+H]+.

Example 2919-(1,2-dimethyl-1H-imidazol-5-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine291 Step 1:4-iodo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and5-iodo-2-methyl-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

To NaH (1.84 g, 76.6 mmol) in a 100 mL of round bottom flask was addedDMF (10 mL) dropwise, 4-iodo-2-methyl-1H-imidazole (8 g, 38.3 mmol) wasadded. After it was stirred for about 1 hour,2-(trimethylsilyl)ethoxymethyl chloride (5.36 g, 45.9 mmol) was addeddropwise at 0° C. The temperature was allowed to warm up to r.t. slowly,and stirred at r.t. for 2 h. The reaction mixture was poured into waterand extracted with EtOAc. The organic phase was dried over anhydrousNa2SO4, concentrated, and purified by column chromatography(hexanes/EtOAc=5:1) to give a mixture of4-iodo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and5-iodo-2-methyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazole whichwas used directly for next step (7.8 g, 63%). LC-MS m/z 339 [M+H+]

Step 2: 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-(trimethylstannyl)-1H-imidazole and2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-5-(trimethylstannyl)-1H-imidazole

To a mixture of4-iodo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and5-iodo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.29g, 3.8 mmol) in DCM (15 mL) was added ethylmagnesium bromide (1.9 mL, 3mol/L, 5.7 mmol) at −78° C. The temperature of the mixture was allowedto warm up to about 10° C. slowly. After it was cooled to −78° C.,trimethyltin chloride (6.5 ml, 1 mol/L, 6.5 mmol) was added dropwise.After the temperature was allowed to slowly warm up to room temperatureand the reaction mixture was pouted into saturate NH4Cl solution andextracted with DCM. The organic was washed with water twice, dried overanhydrous Na2SO4, and concentrated to give the mixture of2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-(trimethylstannyl)-1H-imidazole and2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-5-(trimethylstannyl)-1H-imidazole (1.0 g, 70%). LC-MS m/z 377 [M+H+]

Step 3:2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

A mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), a mixture of2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-(trimethylstannyl)-1H-imidazole and2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-5-(trimethylstannyl)-1H-imidazole (600 mg, 1.6 mmol) in dioxane (2 mL) was bubbledwith N2 for about 2 min and then it was stirred at 120° C. for 35 minunder the microwave irradiation. It was filtered, concentrated andpurified by prep-TLC (EtOAc) to give2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(238 mg, 59%). LC-MS m/z 506 [M+H+]

Step 4:2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine271

A solution of HCl in MeOH (4 mol/L, 3 mL, 12 mmol) was added dropwise toa solution of2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine271 (360 mg, 0.71 mmol) in ethanol (3 mL) at 0° C. After 30 min, thetemperature was allowed to warm up to 70° C. and stirred at 70° C.overnight. It was concentrated, basified with TEA, and purified byprep-TLC to give2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine271 (240 mg, 91%). 1H NMR (MeOD, 400 MHz): δ 8.72 (s, 1H), 8.60 (d,J=4.4 Hz, 1H), 8.19 (s, 1H), 7.87 (s, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.46(s, 1H), 5.72-5.72 (m, 1H), 4.65-4.64 (m, 2H), 4.60-4.59 (m, 2H), 2.68(s, 3H), 1.63-1.62 (d, J=6.8 Hz, 6H). LC-MS m/z 376 [M+H+]

Step 5

Following the procedures for Example 282, to sodium hydride NaH (12 mg,0.5 mmol) in a 100 mL round bottom flask was added DMF (6 mL) dropwise2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine271 (100 mg, 0.25 mmol) was added. After it was stirred for 1 h,iodomethane (48 mg, 0.33 mmol) in THF was added dropwise at 0° C. Themixture was allowed to warm up to room temperature slowly and stirredfor 2 hours. The reaction mixture was poured into water, extracted withEtOAc. The organic phase was dried over anhydrous Na2SO4, concentrated,and purified by prep-TLC (EtOAc) to give 282 (50 mg, 51%) and 291 (15mg, 15%). 1H NMR (CDCl3, 400 MHz): δ 8.57 (d, J=8.0 Hz, 1H), 7.87 (s,1H), 7.87 (s, 1H), 7.69 (s, 1H), 7.16 (d, J=6.8 Hz, 1H), 7.06-7.04 (m,2H), 6.02-5.96 (m, 1H), 4.54-4.52 (m, 2H), 4.48-4.47 (m, 2H), 3.59 (s,3H), 2.46 (s, 3H), 1.60 (d, J=6.8 Hz, 6H). LC-MS m/z 389 [M+H+]

Example 2921-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropan-2-ol292

To a stirred suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoro acetate (300 mg, 0.61 mmol) in THF (8 mL) was added lithiumperchlorate (65 mg, 0.61 mmol) and DIPEA (0.21 mL, 1.21 mmol) followedby 1,2-epoxy-2-methylpropane (0.54 mL, 0.81 mmol) and the mixturestirred at RT for 5 h before the addition of water (2.5 mL). Afterstirring for a further 18 h then DIPEA (0.16 mL, 0.92 mmol) added andthe mixture heated at 45° C. for 5 h then at RT for 72 h. The reactionmixture was diluted with DCM and washed with water before being dried(MgSO4), filtered and concentrated in vacuo. The resultant residue wassubjected to flash chromatography (SiO2, preconditioned with 25% TEA inDCM, gradient 0 to 5% methanol in DCM) then freeze dried frommethanol/water and triturated in petroleum ether to give 292 as a creamsolid (92 mg, 34%). LCMS: RT=2.76 min, [M+H]+=451. ¹H NMR 400 MHz(DMSO-d) δ: 8.32 (1 H, d, J=8.28 Hz), 7.90 (2 H, d, J=2.80 Hz), 7.05 (1H, dd, J=8.35, 1.77 Hz), 6.90 (1 H, d, J=1.70 Hz), 7.27-4.48 (1 H, m),4.49 (4 H, q, J=5.87 Hz), 4.03 (1 H, s), 3.04 (2 H, d, J=10.80 Hz), 2.46(1 H, s), 2.23 (4 H, s), 1.70 (4 H, s), 1.48 (6 H, d, J=6.59 Hz), 1.10(6 H, s)

Example 2932-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)ethanol293

To a stirred suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoro acetate (300 mg, 0.61 mmol) in DMF (3.5 mL) was addedpotassium carbonate (290 mg, 2.1 mmol) and2-(2-bromoethoxy)tetrahydro-2H-pyran and the mixture heated at 60° C.for 18 h before being diluted with DCM. The resultant solution waswashed with saturated aqueous sodium hydrogen carbonate, water and thenbrine before being dried (MgSO4), filtered and concentrated in vacuo.The resultant residue was subjected to flash chromatography (SiO2,gradient 0 to 8% methanol in DCM) to give2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneas a cream solid (147 mg, 48%). 1H NMR 400 MHz (CDCl3) δ: 8.44 (1 H, d,J=8.29 Hz), 7.87 (1 H, s), 7.63 (1 H, s), 7.04 (1 H, dd, J=8.33, 1.81Hz), 6.92 (1 H, d, J=1.75 Hz), 6.01-6.00 (1 H, m), 4.63 (1 H, t, J=3.54Hz), 4.46-4.45 (4 H, m), 3.92-3.91 (2 H, m), 3.65 (1 H, m), 3.57-3.49 (1H, m), 3.15 (2 H, m), 2.73 (2 H, m), 2.53 (1 H, m), 2.25 (2 H, m), 1.87(5 H, m), 1.73-1.69 (3 H, m), 1.60 (8 H, m).

A solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(371 mg, 0.73 mmol) in methanol (3.5 mL) was treated with 4N HCl indioxane (3.5 mL) and the mixture stirred for 45 min before beingconcentrated in vacuo. The resultant residue was re subjected to thereaction conditions as before and stirred for 1 h at RT before beingconcentrated in vacuo. The resultant residue was partitioned betweenDCM/saturated aqueous sodium hydrogen carbonate, the aqueous extractedtwice with DCM and the combined organic extracts washed with brine andthen dried (Na2SO4), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, columnpreconditioned with 1% TEA in DCM, gradient 0 to 7% methanol in DCM) togive 293 as a yellow foam (94 mg, 30%). LCMS: RT=2.61 min, [M+H]+=423.¹H NMR 400 MHz (DMSO-d) δ: 8.32 (1 H, d, J=8.28 Hz), 7.89 (2 H, d,J=1.96 Hz), 7.05 (1 H, dd, J=8.31, 1.76 Hz), 6.89 (1 H, d, J=1.71 Hz),5.88-5.87 (1 H, m), 4.49 (4 H, q, J=5.91 Hz), 3.53 (2 H, t, J=7.21 Hz),3.03 (2 H, d, J=11.27 Hz), 2.52 (3H, m), 2.16 (2 H, t, J=11.38 Hz), 1.76(2 H, d, J=12.61 Hz), 1.67 (2 H, d, J=12.75 Hz), 1.47 (6 H, d, J=6.60Hz)

Example 2942-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine294

A mixture of trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-ylester (125 mg, 0.54 mmol),8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(200 mg, 0.491 mmol), PdCl2dppf.DCM (41 mg, 0.05 mmol, 10 mol %), cesiumcarbonate (400 mg, 1.23 mmol), DME (2 mL) and water (0.2 mL) was heatedat 80° C. for 90 min. The cooled reaction mixture was diluted with DCM,filtered and concentrated in vacuo. The resultant residue was subjectedto flash chromatography (SiO2, gradient 0 to 100% ethyl acetate incyclohexane) to give8-(3,6-Dihydro-2H-pyran-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(73 mg, 39%). LCMS RT=4.36, [M+H]+=378.

A mixture of8-(3,6-dihydro-2H-pyran-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(73 mg, 0.19 mmol), 20% palladium hydroxide on carbon (50 mg) and ethylacetate (10 mL) was degassed then stirred at RT for 72 h under anatmosphere of hydrogen. The reaction mixture was filtered, the filtrateconcentrated in vacuo and the residue triturated in cyclohexane to give294 as a white solid (51 mg, 71%). LCMS: RT=4.30 min, [M+H]+=380 ¹H NMR400 MHz (DMSO-d) δ: 8.34 (1 H, d, J=8.29 Hz), 7.91 (2 H, d, J=1.36 Hz),7.08 (1 H, dd, J=8.34, 1.79 Hz), 6.92 (1 H, d, J=1.73 Hz), 5.90-5.89 (1H, m), 4.50 (4 H, q, J=5.58 Hz), 3.96-3.95 (2 H, m), 3.44 (2 H, td,J=11.21, 3.01 Hz), 2.77-2.76 (1 H, m), 1.73-1.66 (4 H, m), 1.49 (6 H, d,J=6.60 Hz)

Example 295 methyl2-(2-ethoxyphenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate295

Methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80mg, 1 eq), 2-ethoxyphenylboronic acid (66 mg, 1.75 eq), andtetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueoussodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140°C. for 10 min in a sealed microwave reactor. The crude reaction mixturewas concentrated and purified using reverse phase HPLC to yield 295 (9mg). ESI-MS 365.1 (M)+

Example 296 methyl2-(3-isopropylphenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate296

Methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80mg, 1 eq), 3-isopropylphenylboronic acid (65 mg, 1.75 eq), andtetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueoussodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140°C. for 10 min in a sealed microwave reactor. The crude reaction mixturewas concentrated and purified using reverse phase HPLC to yield 296 (4mg). ESI-MS: 363.1 (M)+

Example 297 methyl2-(2-ethylphenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate297

Methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80mg, 1 eq), 2-ethylphenylboronic acid (60 mg, 1.75 eq), andtetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueoussodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140°C. for 10 min in a sealed microwave reactor. The crude reaction mixturewas concentrated and purified using reverse phase HPLC to yield 297 (11mg). ESI-MS: 349.1 (M)+

Example 298 methyl2-(2-isopropylphenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate298

Methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80mg, 1 eq), 2-isopropylphenylboronic acid (65 mg, 1.75 eq), andtetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueoussodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140°C. for 10 min in a sealed microwave reactor. The crude reaction mixturewas concentrated and purified using reverse phase HPLC to yield 298 (23mg). ESI-MS: 363.1 (M)+.

Example 299 methyl2-(3-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate299

Methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80mg, 1 eq), 3-(trifluoromethyl)phenylboronic acid (76 mg, 1.75 eq), andtetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueoussodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140°C. for 10 min in a sealed microwave reactor. The crude reaction mixturewas concentrated and purified using reverse phase HPLC to yield 299 (34mg). ESI-MS: 389.1 (M)+

Example 3002-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetamide300

A mixture of 194 mg (0.500 mmol) of9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411, 0.436 mL (2.00 mmol) of1-(tert-butyldimethylsilyloxy)-1-methoxyethene, 19.6 mg (0.025 mmol) ofdichlorobis(tri-o-tolylphosphine)palladium(II) (19.6 mg, 0.0250 mmol)and 309 mg (1.00 mmol) of tributyltin fluoride (309 mg, 1.00 mmol) in3.0 ml of tetrahydrofuran was degassed and then heated for 18 hours at80° C. The mixture was filtered through Celite, the filtrate mixed with10 ml of water, the mixture was acidified to pH2 and extracted withethyl acetate. The organic phases were combined, dried with MgSO4 andconcentrated. The residue was purified by flash chromatography (0-5%gradient of methanol in dichloromethane) to afford 98 mg of Methyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate(51%). M/z 382.2. calc. 381.18

A mixture of 98 mg (0.257 mmol) of methyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetateand 2.0 ml of 1.0 M of aqueous lithium hydroxide in 6 ml ofmethanol/tetrahydrofuram (1:1) mixture was stirred at 50° C. for 3hours. The mixture was concentrated and acidified to pH 3 by carefuladdition of 1 N aqueous hydrogen chloride. The precipitate was collectedand dried in high vacuum for 18 hours to give2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)aceticacid. Yield 58 mg. M/z 368.2, calc 367.16

A mixture of 58 mg (0.158 mmol) of2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)aceticacid, 76 mg (0.20 mmol) ofN,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate, (HATU, 16 mg, 0.30 mmol) of ammonium chloride and28 uL (0.200 mmol) of Triethylamine in N,N-3.0 ml of Dimethylformamidewas stirred for 40 min. The mixture was concentrated in vacuum andtriturated with 10 ml of water. The solid was collected and purified byRP HPLC (acetonitrile gradient) to give 300. Yield 8.1 mg. M/z 367.2,calc. 366.18. 1H NMR (500 MHz, DMSO) δ 8.30 (d, J=8.2, 1H), 7.86 (s,1H), 7.44 (s, 1H), 7.04 (d, J=8.3, 1H), 6.96 (s, 1H), 6.88 (s, 1H), 5.80(dt, J=13.1, 6.5, 1H), 4.49 (q, J=6.2, 4H), 3.38 (s, 2H), 2.25 (s, 3H),1.45 (d, J=6.6, 6H)

Example 3012-(5-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-2-methyl-1H-imidazol-1-yl)ethanol301 Step 1: Preparation of 4,5-diiodo-2-methyl-1H-imidazole

To a rapidly stirred solution of 2-methyl-1H-imidazole (40.0 g, 0.49mol) in DMF (250 mL) was added NIS (119 g, 0.51 mol) in small portionsat 0° C. The temperature of the mixture was allowed to warm up to r.t.slowly and stirred at r.t. for 4 hours. The reaction mixture was pouredinto a saturate Na2CO3 solution, and keep the solution pH>7. The solidwas filtered and dried to give 4,5-diiodo-2-methyl-1H-imidazole (112 g,68.7%). ESI-MS, m/z 335 [M+H+]

Step 2: 4-iodo-2-methyl-1H-imidazole

A mixture of 4,5-diiodo-2-methyl-1H-imidazole (40.0 g, 119.4 mmol) andNa2SO3 (120.4 g, 0.96 mmol) in DMF (250 mL) was stirred at 110° C. underN2 overnight. The solid was filtered off, and the filtrate wasconcentrated and poured into water, extracted with EtOAc. The combinedorganic layer was washed with water, dried over Na2SO4, concentrated andpurified by silica gel chromatography to give4-iodo-2-methyl-1H-imidazole (15.3 g, 61%)

Step 3:4-iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazoleand5-iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazole

A mixture of 4-iodo-2-methyl-1H-imidazole (1.0 g, 4.8 mmol), Cs2CO3(0.78 g, 2.4 mmol), 2-(2-Bromo-ethoxy)-tetrahydro-pyran (1.5 g, 6.0mmol) in DMF (10 mL) was stirred at 70° C. for 4 h. The reaction mixturewas concentrated, poured into water, extracted with EtOAc. The combinedorganic layer was washed with brine and concentrated. It was purified bychromatography to give the mixture of4-iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazole(0.6 g, 37%) which was contaminated with some of5-iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazolethat was difficult to separate. 1H NMR (CDCl3, 400 MHz): δ 6.97 (s, 1H),4.54 (t, J=3.2 Hz, 1H), 3.95-3.94 (m, 2H), 3.93-3.91 (m, 1H), 3.60-3.56(m, 2H), 3.48-3.43 (m, 1H), 2.40 (s, 1H), 1.75-1.54 (m, 6H). LC-MS: m/z337 [M+H+]

Step 4:2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethylstannyl)-1H-imidazoleand2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(trimethylstannyl)-1H-imidazole

To a mixture of4-iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazoleand5-iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazole(500 mg, 1.9 mmol) in DCM (10 mL) was added ethyl magnesium bromide (0.7ml, 3 mol/L, 2.2 mmol) at −78° C. The mixture was allowed to warm up toabout 10° C. slowly. After cooled to −78° C. again, trimethyltinchloride (2.2 mL, 1 mol/L, 2.2 mmol) was added dropwise. After addition,the mixture was allowed to slowly warm up to room temperature. Thereaction mixture was poured into a saturate NH4Cl solution, andextracted with DCM. The combined organic layer was washed with watertwice, dried over anhydrous Na2SO4 and concentrated to give2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethylstannyl)-1H-imidazole(0.44 g, 63%) 1H NMR (CDCl3, 400 MHz): δ 6.93 (s, 1H), 4.54-4.53 (m,1H), 4.05-4.03 (m, 2H), 3.97-3.93 (m, 1H), 3.61-3.59 (m, 2H), 3.45-3.39(m, 1H), 2.44 (s, 3H), 1.66-1.47 (m, 6H), 0.26 (s, 9H). LC-MS, m/z 375[M+H+], which was contaminated with some2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(trimethylstannyl)-1H-imidazole.

Step 5

2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(left below) and2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(right below)

A mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), and2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethylstannyl)-1H-imidazole(600 mg, 1.6 mmol) in dioxane (2 mL) was bubbled with N2 for about 2min. The mixture was then stirred at 120° C. for 35 min under microwaveirradiation. The mixture was filtered, concentrated and purified byprep-TLC (EtOAc) to give the mixture of2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(left above) and2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(right above) (total 130 mg, 32%). 1H NMR (CDCl3, 400 MHz): δ 8.44-8.42(m, 1H), 7.81 (s, 1H), 7.58 (s, 1H), 7.48-7.46 (m, 1H), 7.42 (d, J=1.6Hz, 1H), 7.19 (s, 1H), 4.51-4.95 (m, 1H), 4.45-4.44 (t, 1H), 4.39-4.38(m, 2H), 4.38-4.37 (m, 2H), 4.07-4.04 (m, 2H), 4.00-4.97 (m, 1H),3.63-3.54 (m, 2H), 3.40-3.36 (m, 1H), 2.49 (s, 3H), 1.76-1.6 (m, 4H),1.48-1.47 (m, 2H). LC-MS, m/z 504 [M+H+]

Step 6

The mixture of2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(left above) and2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(right above) (90 mg, 0.18 mmol) was dissolved in methanol (3 mL) and aHCl solution in MeOH (4 mol/L, 3.0 mL) was added dropwise at 0° C. Themixture was allowed to warm up to room temperature slowly and stirred atroom temperature for 2 h. It was concentrated and the residue was washedwith EtOAc to give 255 (65 mg, 72%) and 301 (20 mg, 21%) as HCl salts.301: 1H NMR (CDCl3, 400 MHz): δ 8.54 (d, J=8.4 Hz, 1H), 7.85 (s, 1H),7.66 (s, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.11 (s, 1H), 6.89 (s, 1H),6.04-5.95 (m, 1H), 4.51-4.45 (m, 4H), 4.12-4.06 (m, 2H), 3.78-3.74 (m,2H), 2.44 (s, 3H), 1.60 (d, J=6.4 Hz, 6H). LC-MS m/z 420 [M+H+]

Example 3021-(4-(2-(1-isopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol302

Step 1

To a mixture of8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid(1.92 g, 6.2 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butylester (1.30 g, 7.5 mmol) in DMF (20 mL) at 0° C. was added DIPEA (2.70mL, 15.5 mmol) and HATU (3.54 g, 9.3 mmol). The reaction mixture wasstirred for 7 h at RT before the addition of DMF (40 mL) and stirringovernight. The reaction mixture was concentrated in vacuo and theresultant residue partitioned between DCM and water. The aqueous phasewas extracted with DCM (×2) before the combined organic extracts werewashed sequentially with 10% citric acid solution, saturated sodiumbicarbonate solution then brine, dried (Na2SO4) and concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 0-90% ethyl acetate in cyclohexane) to giveN′-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylicacid tert-butyl ester as a white solid (3.02 g, quantitative yield).LCMS RT=4.76 min, [M+H]+=465/467. ¹H NMR 400 MHz (DMSO-d6) δ: 8.62 (1 H,s), 8.40 (1 H, d, J=8.59 Hz), 7.69 (1 H, s), 7.23-7.22 (2 H, m), 4.81 (1H, s), 4.44 (4 H, s), 1.32 (9 H, s), 1.13 (6 H, d, J=6.64 Hz)

Step 2

A solution ofN′-(8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylicacid tert-butyl ester (2.71 g, 5.83 mmol) in methanol (52 mL) wastreated with 4N HCl in dioxane (5.83 mL, 23.3 mmol). The reactionmixture was stirred at 50° C. overnight before the reaction wasconcentrated in vacuo and the resultant residue triturated with diethylether to give8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidN-isopropyl-hydrazide dihydrochloride as a pale yellow foam (2.69 g,quantitative yield). LCMS RT=4.17 min, [M+H]+=365/367

Step 3

A suspension of8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidN-isopropyl-hydrazide dihydrochloride (2.69 g, 6.1 mmol) in DCM (61 mL)was treated with TEA (3.84 mL, 27.6 mmol). The resultant solution wascooled to 0° C. before methoxyacetyl chloride (1.12 mL, 12.3 mmol) wasadded dropwise and the reaction stirred at 0° C. for 1.75 h. Thereaction was quenched with saturated sodium bicarbonate solution and thephases separated. The aqueous phase was extracted with DCM (×2) beforethe combined organic phases were washed sequentially with 10% citricacid solution, saturated sodium bicarbonate solution and brine. Theorganic solution was dried (Na2SO4), concentrated in vacuo and theresultant solid was triturated with diethyl ether to give8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidN-isopropyl-N′-(2-methoxy-acetyl)-hydrazide as an off-white solid (2.29g, 5.24 mmol, 86%). LCMS RT=4.29 min, [M+H]+=437/439. ¹H NMR 400 MHz(DMSO-d) δ: 9.61 (1 H, s), 8.29 (1 H, d, J=8.63 Hz), 7.71 (1 H, s), 7.27(1 H, dd, J=8.64, 2.06 Hz), 7.21 (1 H, d, J=2.06 Hz), 4.84 (1 H, t,J=6.91 Hz), 4.45 (4 H, s), 3.92 (2 H, s), 3.33 (3 H, s), 1.15 (6 H, d,J=6.66 Hz)

Step 4

8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidN-isopropyl-N′-(2-methoxy-acetyl)-hydrazide (1.00 g, 2.29 mmol) wassuspended in phosphorus (V) oxychloride (23 mL) then stirred at 100° C.for 18 h. The reaction mixture was concentrated in vacuo and the residuethen azeotroped with toluene (×3) giving a brown solid. To the brownsolid was added acetic acid (23 mL) and ammonium chloride (1.76 g, 22.9mmol), the resultant mixture was stirred at 125° C. for 2.5 h thenfurther ammonium chloride (0.88 g, 11.4 mmol) added, the reaction wasstirred at 125° C. for 1 h, then concentrated in vacuo. The resultantresidue was treated with water and extracted with DCM (×3). The combinedorganic extracts were washed with saturated aqueous sodium bicarbonatesolution then followed by brine then dried (Na2SO4) and concentrated invacuo. The resultant solid was triturated with diethyl ether to give8-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneas a light brown solid (0.73 g, 1.74 mmol, 76%). LCMS RT=4.95 min,[M+H]+=418/420. ¹H NMR 400 MHz (DMSO-d6) δ: 8.29 (1 H, d, J=8.65 Hz),7.93 (1 H, s), 7.31 (1 H, dd, J=8.66, 2.05 Hz), 7.25 (1 H, d, J=2.05Hz), 5.79-5.78 (1 H, m), 4.49 (4 H, s), 4.33 (2 H, s), 3.27 (3 H, s),1.43 (6 H, d, J=6.60 Hz)

Step 5

A mixture of8-bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(100 mg, 0.24 mmol),2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol(127 mg, 0.48 mmol), PdCl2(dppf).DCM (9.8 mg, 0.012 mmol), cesiumcarbonate (234 mg, 0.72 mmol), DME (1.6 mL), water (0.27 mL) and IMS(0.5 mL) was degassed and then heated at 140° C. for 20 min usingmicrowave irradiation. The reaction mixture was partitioned between DCMand water, the aqueous extracted twice with DCM and the combined organicextracts washed with brine then dried (Na2SO4), filtered andconcentrated in vacuo. The resultant residue was subjected to RPHPLC(C18 column, gradient 5 to 95% methanol in water+0.1% HCO2H) to give 302as a white solid (40 mg, 35%). LCMS: RT=3.77 min, [M+H]+478. ¹H NMR 400MHz (DMSO-d) δ: 8.37 (1 H, d, J=8.38 Hz), 8.17 (1 H, s), 7.94 (2 H, d,J=7.28 Hz), 7.40 (1 H, dd, J=8.37, 1.80 Hz), 7.28 (1 H, d, J=1.77 Hz),5.89-5.88 (1 H, m), 4.74 (1 H, s), 4.53 (4 H, m), 4.38 (2 H, s), 4.04 (2H, s), 3.32 (3 H, s), 1.49 (6 H, d, J=6.60 Hz), 1.10 (6 H, s).

Example 303(3R,4R)-4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-3-ol303

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.05 g, 2.21 mmol) was partially dissolved in drydiethyleneglycol dimethyl ether (25 mL) and a solution of borane/THFcomplex (1M in THF, 13.2 mL, 13.2 mmol) was added dropwise. Afterstirring briefly at room temperature, the mixture was allowed to standfor 16 h. The mixture was then cooled in ice, and water (2 mL), 2Msodium hydroxide (6.5 mL) and 35% hydrogen peroxide (1.7 mL, 16.24 mmol)were added dropwise in sequence. The mixture was heated at 50° C. for 6h, then cooled, diluted with water (approx. 45 mL) and extracted threetimes with ethyl acetate. The combined organic extracts were dried(Na2SO4) and concentrated. The resultant residue was subjected to flashchromatography (SiO2, gradient 0-8.5% methanol in DCM) to give the crudeproduct (0.78 g, 71%), containing approx. 20% of 4-hydroxypiperidineisomer which was recrystallised twice from ethyl acetate/methanol togiveracemic-trans-3-Hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester containing <5% of the cis isomer (0.38 g). LCMSRT=4.44, [M+H]+=495. ¹H NMR 400 MHz (DMSO-d6) δ: 8.39 (1 H, d, J=8.25Hz), 7.89 (1 H, s), 7.47 (1 H, d, J=2.62 Hz), 7.03 (1 H, dd, J=8.29,1.80 Hz), 6.77 (1 H, s), 6.07-5.99 (1 H, m), 4.37-4.37 (6 H, m),4.19-4.18 (1 H, m), 3.73-3.73 (1 H, m), 2.66-2.66 (3 H, m), 1.81-1.81 (1H, m), 1.61 (6 H, d, J=6.01 Hz), 1.50 (9 H, s)

To a solution oftrans-racemic-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (180 mg, 0.36 mmol) in DCM (1 mL) and methanol(0.6 mL) was added 4M HCl in dioxane (1.6 mL) slowly and the reactionmixture stirred at RT for 2.5 hr before being concentrated in vacuo. Theresultant residue was triturated in diethyl ether to give4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-3-olwhich was resolved to give the (3R,4R) enantiomer 303 as a white solid(172 mg, quantitative). LCMS: RT=2.41 min, [M+H]+395. ¹H NMR 400 MHz(DMSO-d6) δ: 9.30 (1H, br, s), 9.10 (1H, br, s), 8.36 (1 H, d, J=8.28Hz), 8.10 (1H, br, s), 8.06 (1 H, s), 7.04 (1 H, d, J=8.38 Hz), 6.91 (1H, s), 5.87 (1H, m), 4.53 (4 H, d, J=8.12 Hz), 3.90 (1H, br, m), 3.25(2H, m), 2.78 (1H, m), 2.52 (2H, m), 1.80 (2H, m), 1.50 (1 H, d, J=6.58Hz)

Example 304racemic-trans-2-(3-hydroxy-4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide304

Following the procedure for Example 330,trans-racemic-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-olhydrochloride (0.15 g, 0.35 mmol) was reacted withN,N-dimethyl-2-chloroacetamide (46 mg, 0.38 mmol) to give 304 (135 mg,80%). LCMS: RT=2.50 min, [M+H]+=480. 1H NMR 400 MHz (CDCl3) δ: 8.40 (1H, d, J=8.26 Hz), 7.86 (1 H, s), 7.43 (1 H, s), 7.08-7.03 (1 H, m), 6.82(1 H, d, J=1.72 Hz), 6.02 (1 H, m), 4.38 (4 H, m), 4.10 (1H, br, m),3.38 (2 H, m), 3.31 (2 H, m), 3.09 (3 H, s), 3.00 (1 H, m), 2.98 (3 H,s), 2.47 (2H, m), 1.86 (2 H, m), 1.60 (6 H, dd, J=6.59, 2.76 Hz)

Example 3052-(5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)acetamide305

8-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene with2-Carbamimidoyl-acetamide hydrochloride and isopropylhydrazinehydrochloride were reacted following Example 420. The crude product waspurified by reverse phase HPLC to give 305 (29 mg obtained). LCMS:433.0. 1H NMR (500 MHz, DMSO) δ 8.33 (d, J=8.6 Hz, 1H), 7.95 (s, 1H),7.39 (s, 1H), 7.35 (dd, J=8.7, 2.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 6.97(s, 1H), 5.79 (dt, J=13.2, 6.6 Hz, 1H), 4.53 (s, 4H), 3.45 (s, 2H), 1.47(d, J=6.6 Hz, 6H)

Example 3065-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10-yl)pyridin-2(1H)-one306

10-Chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine(85.0 mg, 0.257 mmol) dissolved in Acetonitrile (2 mL, 50 mmol) andWater (2 mL, 100 mmol) with dissolved Potassium acetate (85.5 mg, 0.871mmol). Degas by bubbling nitrogen for 5 min. 2-Fluoropyridine-5-boronicacid (47.1 mg, 0.334 mmol) was added, thenTetrakis(triphenylphosphine)palladium(0) (4.0E1 mg, 0.035 mmol). Thereaction was microwaved at 145 C 35 min, cooled to RT, and extractedwith ethyl acetate. Combined organics were concentrated to give fluorointermediate,10-(6-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine,which was dissolved in 1,2-Dimethoxyethane (3.00 mL, 28.9 mmol). 10%aqueous HCl (3 mL) was added. The reaction was allowed to stir and heatat 80° C. overnight. The reaction was allowed to cool to roomtemperature and concentrated under reduced pressure to give 306,analyzed by rHPLC. MS: (ESI+)=390.1

Example 3074-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10-yl)piperazin-2-one307

A solution of10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine(80.0 mg, 0.242 mmol), piperazin-2-one (48.4 mg, 0.484 mmol), XPhos(23.0 mg, 0.0484 mmol), and Sodium-tert-butoxide (46.5 mg, 0.484 mmol)in was heated in microwave at 125 C for 30 min. The reaction wasfiltered thru celite then rinsed with EtOAc. The filtrate was washedwater, brine. The organic layer was dried Na2SO4, concentrated to give307, analyzed by rHPLC. MS: (ESI+)=395.2. ¹H NMR (500 MHz, DMSO) δ 8.06(s, 1H), 8.03 (d, J=5.7 Hz, 2H), 7.93 (s, 1H), 7.59 (s, 1H), 5.72 (dt,J=13.1, 6.6 Hz, 1H), 4.62-4.52 (m, 2H), 4.51-4.39 (m, 2H), 3.94 (s, 2H),3.73-3.62 (m, 2H), 3.37-3.30 (m, 2H), 1.51 (d, J=6.6 Hz, 6H).

Example 3082-(4-(2-(1-isopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)acetamide308

Step 1

8-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(250 mg, 0.60 mmol), 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acidpinacol ester (370 mg, 1.20 mmol), cesium carbonate (585 mg, 1.79 mmol)and 1,1′-bis(diphenylphosphino)ferrocenepalladium (ii)dichloride,dichloromethane (24 mg, 0.03 mmol) were suspended in DME (4.0 mL), IMS(1.3 mL) and water (0.68 mL) and the reaction mixture purged with argon.The reaction mixture was heated using microwave irradiation in a sealedtube at 140° C. for 20 min. The reaction mixture was washed with water,extracted with DCM (2×15 mL) and the combined organics were washed withbrine, dried (Na2SO4) then concentrated in vacuo. The resultant residuewas subjected to flash chromatography (SiO2, eluting with 5% methanol inDCM) to yield4-[2-(2-Isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester as a brown foam (224 mg, 72%). LCMS: RT=5.08 min,[M+H]+=521

Step 2

To a solution of4-[2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (224 mg, 0.43 mmol) in IMS (3 mL) was added acatalytic amount of palladium on carbon (10% by wt) and the reactionmixture stirred under an atmosphere of hydrogen at 50° C. for 16 h. Thereaction mixture was filtered and the solids washed with IMS (10 mL).The filtrate was concentrated in vacuo and the resultant residuesubjected to flash chromatography (SiO2, eluting with 2% MeOH in DCM) toyield4-[2-(2-Isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester as a yellow oil (162 mg, 72%). LCMS: RT=5.05 min,[M+H]+=523

Step 3

To a solution of4-[2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (158 mg, 0.30 mmol) in DCM (1.5 mL) was addedtrifluoroacetic acid (1.5 mL, 20.2 mmol) and the reaction mixturestirred at RT for 30 min. The reaction mixture was concentrated in vacuoand the residue azeotroped with ether. The resultant oil was trituratedwith diethyl ether to give2-(2-Isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetate salt as a solid which was collected by filtration (103mg, 64%). LCMS RT=3.03 min, [M+H]+=423. ¹H NMR 400 MHz (DMSO-d) δ: 8.56(1 H, s), 8.33 (1 H, d, J=8.33 Hz), 7.90 (1 H, s), 7.00 (1 H, dd,J=8.38, 1.78 Hz), 6.85 (1 H, d, J=1.73 Hz), 5.81-5.80 (1 H, m), 4.46 (4H, d, J=2.51 Hz), 4.33 (2 H, s), 3.34 (2 H, d, J=12.58 Hz), 3.27 (3 H,s), 2.98-2.95 (2 H, m), 2.82 (1 H, t, J=11.91 Hz), 1.93 (2 H, d, J=13.66Hz), 1.75 (2 H, t, J=12.95 Hz), 1.44 (6 H, d, J=6.60 Hz)

Step 4

A suspension of2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoroacetate salt (99 mg, 0.18 mmol) in THF (1.8 mL) was treatedwith 2-bromoacetamide (109 mg, 0.2 mmol) followed by potassium carbonate(56 mg, 0.41 mmol) and the reaction mixture stirred at RT before beingdiluted with DCM and water. The aqueous layer was extracted twice withDCM and the combined organic extracts washed with saturated aqueoussodium bicarbonate followed by brine then dried (Na2SO4), filtered andconcentrated in vacuo. The resultant residue was dissolved in methanol,the solution cooled to 0° C. and treated with water to form aprecipitate which was filtered off and washed with cold methanol/waterto give a white solid. The solid was azeotroped with methanol thendiethyl ether to give 308 as a white solid (38 mg, 43%). LCMS: RT=2.66min, [M+H]+=480. ¹H NMR 400 MHz (DMSO-d6) δ: 8.39 (1 H, d, J=8.32 Hz),8.16 (1 H, s), 7.09-7.08 (1 H, m), 6.97 (1 H, s), 5.76-5.74 (1 H, m),4.58 (4 H, d, J=14.42 Hz), 4.51 (2 H, s), 3.96 (2 H, s), 3.60 (2 H, d,J=11.71 Hz), 3.37 (3 H, s), 3.20 (2 H, m), 2.86 (1 H, m), 2.03 (4 H, m),1.53 (6 H, d, J=6.57 Hz)

Example 3092-(1-isopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine309

Step 1

A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(2.00 g, 5.1 mmol), 2-methoxy-acetamidine hydrochloride (0.76 g, 6.1mmol) and TEA (5.00 mL, 35.9 mmol) in DMF (38 mL) was evacuated andrefilled with nitrogen (×3). The reaction was treated with Xantphos(0.15 g, 0.26 mmol) and palladium (II)acetate (57 mg, 0.26 mmol) beforethe reaction was purged with carbon monoxide gas and the reactionstirred at 60° C. for 3.5 h. The reaction mixture was cooled to RT,purged with nitrogen then treated with isopropyl-hydrazine hydrochloride(1.70 g, 15.0 mmol) and acetic acid (19 mL). After stirring at 60° C.for 1.5 h the reaction was diluted with ethyl acetate (350 mL). Thesolution was washed with 1N NaOH (2×50 mL) followed by brine (50 mL),then dried (Na2SO4) and concentrated in vacuo. The resultant residue wassubjected to flash chromatography (SiO2, gradient 0-3% methanol in DCM)then triturated with diethyl ether to afford9-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneas a pale pink solid (0.85 g, 2.0 mmol, 40%). LCMS RT=4.95 min,[M+H]+=418/420. ¹H NMR 400 MHz (DMSO-d6) δ: 8.44 (1 H, d, J=2.57 Hz),7.94 (1 H, s), 7.43 (1 H, dd, J=8.74, 2.58 Hz), 6.99 (1 H, d, J=8.74Hz), 5.72-5.63 (1 H, m), 4.49 (4 H, d, J=3.06 Hz), 4.33 (2 H, s), 3.27(3 H, s), 1.44 (6 H, d, J=6.60 Hz).

Step 2

To a suspension of9-bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(0.85 g, 2.0 mmol) in IMS (20 mL) was added DCM (6 mL). The mixture wasdegassed with nitrogen before being treated with palladium on carbon(10% palladium, 50% water, 350 mg). The vessel was evacuated andrefilled with hydrogen and stirred at RT18 h before further catalyst wasadded and the reaction stirred for 72 h. The reaction was filtered thenconcentrated in vacuo to give 309 as a pale yellow solid (0.73 g,quantitative yield). LCMS RT=4.55 min, [M+H]+=340. ¹H NMR 400 MHz(DMSO-d6) δ: 8.37 (2 H, dd, J=9.88, 1.75 Hz), 7.30 (1 H, ddd, J=7.93,7.18, 1.70 Hz), 7.12-7.12 (1 H, m), 7.03 (1 H, dd, J=8.19, 1.22 Hz),5.83-5.74 (1 H, m), 4.48-4.47 (4 H, m), 4.36 (2 H, s), 3.28 (3 H, s),1.45 (6 H, d, J=6.60 Hz)

Example 3139-bromo-2-(3-cyclopropyl-1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine313

8-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene withCyclopropanecarboxamidine hydrochloride and isopropylhydrazinehydrochloride were reacted following Example 420. The crude product waspurified by reverse phase HPLC to give 313 (75 mg obtained). LCMS:414.0. 1H NMR (400 MHz, DMSO) δ 8.30 (m, H), 7.90 (s, 1H), 7.35 (dd,J=8.7, 2.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 5.75 (dt, J=13.2, 6.6 Hz,1H), 4.51 (m. 4H), 2.02-1.91 (m, 1H), 1.45 (d, J=6.6 Hz, 6H), 0.93-0.85(m, 2H), 0.84-0.77 (m, 12H)

Example 3149-(1-ethylpiperidin-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine314

To a stirred suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoro acetate (189 mg, 0.37 mmol) in DCE (3 mL) was added aceticacid (3 drops, catalytic) acetaldehyde (0.023 mL, 0.41 mmol) and sodiumtriazetoxyborohydride (94 mg, 0.44 mmol). After stirring for 2 h at RTDCM was added and the mixture washed with saturated aqueous sodiumhydrogen carbonate, water and then brine before being dried (MgSO4),filtered and concentrated in vacuo. The resultant residue was subjectedto flash chromatography (SiO2, gradient 0 to 20% methanol in DCM) thenfreeze dried from methanol/water and triturated in petroleum ether togive 314 as a brown solid (18 mg, 12%). LCMS: RT=2.73 min, [M+H]+=407.¹H NMR 400 MHz (DMSO-d) δ: 8.32 (1 H, d, J=8.29 Hz), 7.90 (2 H, d,J=2.38 Hz), 7.06 (1 H, d, J=8.41 Hz), 6.90 (1 H, s), 5.90-5.89 (1 H, m),4.49 (4 H, d, J=7.47 Hz), 2.97 (2 H, d, J=10.98 Hz), 2.34 (2 H, q,J=7.20 Hz), 1.95 (2 H, t, J=11.47 Hz), 1.76 (2 H, d, J=12.54 Hz),1.72-1.54 (3 H, m), 1.48 (6 H, d, J=6.59 Hz), 1.02 (3 H, t, J=7.20 Hz)

Example 315(5-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)methanol315

A solution of8-bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene309 (280 mg, 0.67 mmol) in 48% aqueous HBr (4.19 mL) was heated at 100°C. for 4 h before cooling to RT. The solution was neutralized by theaddition of 1M aqueous sodium carbonate and then extracted with DCM, theorganic layer washed with water then dried (Na2SO4), filtered andconcentrated in vacuo to give[5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanolas a cream solid (162 mg, 60%). LCMS RT=4.74 min, [M+H]+=404. ¹H NMR 400MHz (DMSO-d) δ: 8.30 (1 H, d, J=8.65 Hz), 7.91 (1 H, s), 7.33 (1 H, dd,J=8.65, 2.06 Hz), 7.27 (1 H, d, J=2.03 Hz), 5.82-5.75 (1 H, m), 5.18 (1H, t, J=6.03 Hz), 4.51 (4 H, s), 4.40 (2 H, d, J=5.99 Hz), 1.44 (6 H, d,J=6.60 Hz)

A solution of[5-(8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol(67 mg, 0.17 mmol) in IMS was degassed then treated with Pd/C (10% wt.120 mg) before being stirred at RT under an atmosphere of hydrogen for18 h. The reaction mixture was filtered through Celite®, washing withDCM, the filtrate concentrated in vacuo. The resultant residue wassubjected to flash chromatography (SiO2, gradient 0 to 7% methanol inDCM) to give 315 as a white solid (13 mg, 24%). LCMS: RT=3.79 min,[M+H]+=326. ¹H NMR 400 MHz (DMSO-d) δ: 8.42 (1 H, dd, J=8.03, 1.74 Hz),7.91 (1 H, s), 7.33 (1 H, ddd, J=8.16, 7.12, 1.77 Hz), 7.16-7.16 (1 H,m), 7.06 (1 H, dd, J=8.18, 1.21 Hz), 5.86 (1 H, t, J=6.61 Hz), 5.21 (1H, t, J=6.03 Hz), 4.52 (4 H, q, J=5.81 Hz), 4.42 (2 H, d, J=6.00 Hz),1.48 (6 H, d, J=6.61 Hz)

Example 3163-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanamide316 Step 1: (E)-methyl3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acrylate

A mixture of 0.194 g (0.500 mmol) of9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411, 0.180 mL (2.00 mmol) of methyl acrylate, 22.4 mg (0.0999 mmol) ofpalladium acetate, 122 mg (0.400 mmol) of tri-o-tolylphosphine and 0.278mL, (2.00 mmol) of triethylamine in 4.0 ml of N,N-Dimethylformamide washeated at 100° C. for 6 hours. The mixture was concentrated in vacuumand partitioned between ethyl acetate and water. The organic extractswere washed with dilute aqueous HCl, water, brine, dried over Na2SO4 andconcentrated in vacuum. The residue was purified on 4 g silica columneluting with heptane-ethyl acetate gradient to give (E)-methyl3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acrylate.Yield 0.11 g. M/z 394.2, calc. 393.18

Step 2: Methyl3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoate

A solution of 0.11 g (0.28 mmol) of (E)-methyl3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acrylatein 5 ml of THF/ethanol mixture was subjected to hydrogenation over 100mg of 10% Pd—C for 4 hours. The mixture was filtered through celite; thefiltrate was concentrated in vacuum to give Methyl3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoate.Yield 96 mg. M/z 396.2, calc. 395.20

Step 3:3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoicacid

Methyl3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoatewas treated with lithium hydroxide to give3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoicacid. M/z 382.2, calc. 381.18

Step 4

Following the procedures of Example 300,2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoate,ammonium chloride, and HATU were reacted to give 316. M/z 381.1, calc.380.20. 1H NMR (400 MHz, DMSO) δ 8.29 (d, J=8.2, 1H), 7.85 (s, 1H), 7.28(s, 1H), 7.00 (d, J=8.3, 1H), 6.89 (s, 1H), 6.75 (s, 1H), 5.81 (dt,J=13.1, 6.4, 1H), 4.48 (s, 4H), 2.80 (t, J=7.5, 2H), 2.36 (dd, J=16.8,9.2, 2H), 2.25 (s, 3H), 1.45 (d, J=6.5, 6H)

Example 3179-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine317

A mixture of[9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine-2-carboxamide(0.520 g, 1.96 mmol) and 1,1-Dimethoxy-N,N-dimethylmethanamine (1.305mL, 9.824 mmol) in Toluene (28.2 mL, 265 mmol) was heated under refluxfor 1 hour. LCMS: no stm, major peak m/z 320.1. After cooling, theintermediate was concentrated. A mixture of the intermediate andisopropylhydrazine hydrochloride (0.4345 g, 3.929 mmol) in Acetic acid(18 mL, 320 mmol) was heated at 85° C. for 3 hours. The mixture wascooled and filtered from an insoluble impurity. The mother liquor wasconcentrated in vacuum. The residue was diluted with EtOAc then washedwith water and brine. The organic layer was dried Na2SO4, filtered, andconcentrated to give 317 (264). MS: (ESI+)=331.0. 1H NMR (400 MHz, DMSO)δ 9.29 (s, 1H), 7.97 (d, J=24.4 Hz, 1H), 7.94 (s, 1H), 7.31-7.19 (m,1H), 5.85 (dq, J=13.0, 6.4 Hz, 1H), 4.66 (dd, J=5.2, 2.5 Hz, 2H),4.63-4.54 (m, 2H), 1.48 (d, J=6.6 Hz, 6H).

Example 3181-(5-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)-N,N-dimethylmethanamine318

A suspension of[5-(8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol315 (166 mg, 0.51 mmol) in DCM (5 mL) was treated with Dess-Martinperiodinane (DMP, 238 mg, 0.56 mmol) and resultant solution stirred atRT for 2 h under an atmosphere of nitrogen. The reaction was quenched bythe addition of sodium thiosulphate (620 mg in 1 mL water) before theaddition of further water and extracted twice with DCM. The combinedorganic extracts were washed with water then dried (Na2SO4), filteredand concentrated in vacuo to give5-(4,5-Dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole-3-carbaldehydeas a cream solid (170 mg, quantitative). LCMS: RT=4.30 min, [M+H]+324.¹H NMR 400 MHz (DMSO-d6) δ: 9.91 (1 H, s), 8.43 (1 H, dd, J=8.06, 1.78Hz), 8.11 (1 H, s), 7.34-7.34 (1 H, m), 7.17-7.17 (1 H, m), 7.07 (1 H,dd, J=8.17, 1.23 Hz), 6.03 (1 H, m), 4.57-4.48 (4 H, m), 1.55 (6 H, d,J=6.60 Hz)

A mixture of5-(4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole-3-carbaldehyde(85 mg, 0.26 mmol), acetic acid (catalytic, 2 drops), 4 Å molecularsieves and dimethylamine hydrochloride (24 mg, 0.29 mmol) in THF (5 mL)was stirred at RT for 10 min before the addition of sodiumtriacetoxyborohydride (66 mg, 0.31 mmol). After stirring at RT for afurther 18 h the reaction mixture was diluted with DCM, the organiclayer washed with saturated aqueous sodium bicarbonate followed by waterand then brine, then dried (Na2SO4), filtered and concentrated in vacuo.The resultant residue was subjected to RPHPLC (C18 column, gradient 5 to98% methanol in water+0.1% HCO2H) to give 318 as a white solid (13 mg,14%). LCMS: RT=3.18 min, [M+H]+353. ¹H NMR 400 MHz (DMSO-d6) δ: 8.45 (1H, dd, J=8.02, 1.76 Hz), 7.97 (1 H, s), 7.39-7.32 (1 H, m), 7.19-7.19 (1H, m), 7.09 (1 H, dd, J=8.15, 1.25 Hz), 5.89 (1 H, m), 4.54 (4 H, d,J=2.46 Hz), 3.47 (2 H, s), 2.24 (6 H, s), 1.51 (6 H, d, J=6.59 Hz)

Example 319racemic-cis-2-(3-hydroxy-4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide319

Step 1

Racemic-trans-3-Hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester from Example 328 (containing approx. 24% of4-hydroxypiperidine isomer, 0.32 g, 0.65 mmol) was dissolved in DCM (15mL) and cooled in an ice-bath. Dess-Martin periodinane (0.3 M in DCM,4.33 mL, 1.3 mmol) was added dropwise, the mixture was stirred at 0-10°C. for 7 h, then refrigerated for 16 h. Aqueous sodium bisulphate andsodium bicarbonate (10 mL each) were added and the mixture was stirredat room temperature for 15 min. The phases were separated and theaqueous phase was extracted twice with DCM. Combined organic extractswere washed with brine, dried (Na2SO4) and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient0-5% methanol in DCM) then trituration with ether to give4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3-oxo-piperidine-1-carboxylicacid tert-butyl ester (86 mg). Additional product was recovered from thetrituration liquor (59 mg). Total yield 145 mg (45%). LCMS RT=3.53,[M+H]+=493, [M+H+ MeOH]+=525.

Step 2

A solution of4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3-oxo-piperidine-1-carboxylicacid tert-butyl ester (145 mg, 0.29 mmol) in dry THF (10 mL) was cooledto −78 C and a solution of lithium tri-sec-butylborohydride in THF(L-Selectride®, 1M, 0.30 mL, 0.30 mmol) was added dropwise. The mixturewas stirred at −78° C. for 1 h, then aqueous sodium bicarbonate wasadded dropwise. After warming to room temperature, the mixture wasextracted three times with ethyl acetate. The combined organic extractswere dried (Na2SO4), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0-5%methanol in DCM) to giveracemic-cis-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (92 mg, 64%). LCMS RT=3.39, [M+H]+=495.

Step 3

To a solution ofracemic-cis-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (92 mg, 0.186 mmol) in DCM (0.5 mL) and methanol(0.3 mL) was added slowly a solution of hydrogen chloride in dioxane(4M, 0.8 mL). The mixture was stirred at room temperature for 2 h 20min, then concentrated in vacuo. The resultant residue was trituratedtwice with ether and dried under vacuum to giveracemic-cis-4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-olhydrochloride (86 mg, 108%). LCMS RT=1.93, [M+H]+=395.

Step 4

cis-racemic-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-olhydrochloride (86 mg, 0.19 mmol) was reacted withN,N-dimethyl-2-chloroacetamide (26 mg, 0.21 mmol) to give 319 (51 mg,57%). LCMS: RT=2.58 min, [M+H]+=480. ¹H NMR 400 MHz (DMSO-d) δ: 8.29 (1H, d, J=8.29 Hz), 7.90-7.90 (2 H, m), 7.08 (1 H, dd, J=8.37, 1.72 Hz),6.98 (1 H, d, J=1.65 Hz), 5.89-5.88 (1 H, m), 4.56-4.41 (4 H, m), 4.08(1 H, br), 3.79 (1 H, br), 3.17 (2 H, m), 3.06 (3 H, s), 2.88 (2 H, m),2.82 (3 H, s), 2.62 (1 H, m), 2.39 (1 H, m), 2.22 (2 H, m), 1.53 (1 H,m), 1.48 (6 H, d, J=6.61 Hz)

Example 320racemic-cis-2-(3-hydroxy-4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide320

Following the procedures for Example 330,cis-racemic-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-olhydrochloride (86 mg, 0.19 mmol) was reacted withN,N-dimethyl-2-chloroacetamide (26 mg, 0.21 mmol) to give 320 (51 mg,57%). LCMS: RT=2.58 min, [M+H]+=480. ¹H NMR 400 MHz (DMSO-d6) δ: 8.29 (1H, d, J=8.29 Hz), 7.90-7.90 (2 H, m), 7.08 (1 H, dd, J=8.37, 1.72 Hz),6.98 (1 H, d, J=1.65 Hz), 5.89-5.88 (1 H, m), 4.56-4.41 (4 H, m), 4.08(1 H, br), 3.79 (1 H, br), 3.17 (2 H, m), 3.06 (3 H, s), 2.88 (2 H, m),2.82 (3 H, s), 2.62 (1 H, m), 2.39 (1 H, m), 2.22 (2 H, m), 1.53 (1 H,m), 1.48 (6 H, d, J=6.61 Hz)

Example 3212-((1R,3r,5S)-3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide321

Step 1

A vessel was charged with8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(1.00 g, 2.67 mmol, bis(neopentyl glycolato)diboron (905 mg, 4.01 mmol),potassium acetate (918 mg, 9.35 mmol) and dioxane (12 mL) before thevessel was sealed and degassed with nitrogen for 10 min. To the reactionwas added PdCl2dppf.DCM (109 mg, 0.13 mmol, 5 mol %) and the reactionpurged with nitrogen before being stirred at 90° C. for 65 h. Thereaction mixture was cooled to RT then diluted with DCM (200 mL) andtreated with activated carbon. The mixture was filtered and the filtratewas washed with water, dried (Na2SO4) and concentrated in vacuo to give8-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(1.00 g, 2.46 mmol, 92%). LCMS RT=3.79 min, [M−HCC(CH3)2CH+H]+=340

Step 2

To a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (500 mg, 2.22 mmol) in THF (5 mL) at −78° C. was added1M LiHMDS in THF (2.44 mL, 2.44 mmol) dropwise. The resulting mixturewas stirred at −78° C. for 1 h before the addition of a solution ofN-phenylbis(trifluoromethanesulfonimide) (872 mg, 2.44 mmol) in THF (5mL) dropwise. The reaction mixture was stirred at −78° C. for 4 h beforebeing quenched with saturated sodium bicarbonate solution. The mixturewas extracted with ethyl acetate, dried (MgSO4) and concentrated invacuo before being subjected to flash chromatography (SiO2, gradient0-40% ethyl acetate in cyclohexane). The resultant residue was furtherpurified by flash chromatography (SiO2, gradient 0-100% DCM incyclohexane) to give3-trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylicacid tert-butyl ester (402 mg, 0.56 mmol, 25%). 1H NMR 400 MHz (CDCl3)δ: 6.11 (1 H, s), 4.48 (2 H, m), 3.02 (1H, m), 2.26 (1 H, m), 2.13 (1 H,m), 2.09 (1 H, m), 2.04 (1 H, m), 2.03 (1 H, s), 1.48 (9 H, s)

Step 3

A vessel was charged with8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(237 mg, 0.56 mmol), PdCl2dppf.DCM (46 mg, 0.06 mmol, 10 mol %) andcesium carbonate (456 mg, 1.40 mmol) before being evacuated and refilledwith nitrogen. To the resultant mixture was added a solution of3-trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylicacid tert-butyl ester (402 mg, 0.56 mmol) in DME (2 mL), followed bywater (0.2 mL). The reaction was evacuated and refilled with nitrogenbefore being stirred at 110° C. for 1.5 h. The reaction mixture waspartitioned between ethyl acetate and water, the organic phase wasseparated, dried (MgSO4) and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0-100%ethyl acetate in cyclohexane) to give3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylicacid tert-butyl ester as a colourless oil (177 mg, 0.35 mmol, 63%). LCMSRT=4.84 min, [M+H]+=503

Step 4

To a degassed solution of3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylicacid tert-butyl ester (176 mg, 0.35 mmol) in acetic acid (7 mL) wasadded palladium hydroxide on carbon (20% palladium, 50% water, 62 mg).The vessel was evacuated and refilled with hydrogen gas (×3) before thereaction was stirred at RT for 100 h. The reaction mixture was filteredthrough a pad of Celite®, washing with ethyl acetate, the filtrateconcentrated in vacuo to give a mixture ofendo/exo-3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester as a black gum (177 mg, 0.35 mmol, quantitativeyield). LCMS RT=4.83 min, [M+H]+505

Step 5

To a solution of3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (177 mg, 0.35 mmol) in dioxane (10 mL) was added4M HCl in dioxane (5 mL) and methanol (5 mL). The resultant mixture wasstirred at RT for 18 h before being concentrated in vacuo. The resultantresidue was taken up into methanol and loaded onto a SCX-2 cartridge,eluting with methanol then 2M NH3 in methanol. The basic fractions wereconcentrated in vacuo to give a mixture ofendo/exo-8-(8-aza-bicyclo[3.2.1]oct-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneas a brown glass (91 mg, 0.22 mmol, 64%). LCMS RT=2.77 min and 2.91 min,[M+H]+=405

Step 6

A solution ofendo/exo-8-(8-aza-bicyclo[3.2.1]oct-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(91 mg, 0.22 mmol) in DCM (1 mL) was treated with TEA (38 L, 0.27 mmol)followed by bromoacetamide (37 mg, 0.27 mmol) and the reaction mixturestirred at RT for 22 h before being concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0 to 7% 2MNH3 (methanol) in DCM) and endo/exo isomers separated by RPHPLC(C6-phenyl column, gradient 5 to 25% acetonitrile in water+0.1% HCO2Hover 20 min) to give 321 and 322 as white solids (3 mg and 13 mg of 1stand 2nd eluting isomers respectively). 1st eluting isomer was assignedas 321: LCMS: RT=2.64 min, [M+H]+=462. 1H NMR 400 MHz (CDCl3) δ: 8.45 (1H, d, J=8.40 Hz), 8.10 (1H, br),7.97 (1 H, br), 7.89 (1 H, s), 7.67 (1H, s), 7.14 (1 H, d, J=8.52 Hz), 7.02 (1 H, s), 5.99 (1 H, m), 5.81 (1H, br), 4.49-4.47 (4 H, m), 3.49 (2 H, s), 3.19 (3 H, m), 2.66-2.56 (2H, m), 2.04-1.96 (4 H, m), 1.66 (2 H, m), 1.59 (6 H, d, J=6.63 Hz)

Example 3222-((1R,3S,5S)-3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide322

Following the procedures for Example 321, 2nd eluting isomer wasassigned as 322: LCMS: RT=2.70 min, [M+H]+=462. 1H NMR 400 MHz (CDCl3)δ: 8.45 (1 H, d, J=8.31 Hz), 8.02 (1H,br),7.88 (1 H, d, J=0.67 Hz), 7.74(1 H, br), 7.66 (1 H, s), 7.06 (1 H, dd, J=8.35, 1.82 Hz), 6.93 (1 H, d,J=1.77 Hz), 5.99-5.98 (1 H, m), 5.75 (1 H, br), 4.47-4.46 (4 H, m), 3.42(2 H, m), 3.16 (2 H, s), 2.92-2.90 (1 H, m), 2.10-2.08 (2 H, m), 2.00 (2H, t, J=12.82 Hz), 1.82-1.81 (4 H, m), 1.59 (6 H, d, J=6.63 Hz)

Example 3232-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(4-methylpiperazin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine323

A solution of9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine(66.0 mg, 0.200 mmol;), 1-methyl-piperazine, (88.5 uL, 0.798 mmol) andTriethylamine (167 uL, 1.20 mmol) in N,N-Dimethylacetamide (3.00 mL,32.3 mmol) was heated in microwave at 160 C for 20 min. The reaction wasfiltered thru celite then rinsed with EtOAc. The filtrate was washedwater, brine. The organic layer was dried Na2SO4, concentrated. Thecrude product was purified by rHPLC to give 323. MS: (ESI+)=395.2. 1HNMR (400 MHz, DMSO) δ 8.50 (d, J=8.7 Hz, 1H), 7.88 (s, 1H), 7.80 (s,1H), 6.72 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.7 Hz, 1H), 4.49 (m,4H), 3.61-3.48 (m, 4H), 2.42-2.34 (m, 4H), 2.21 (s, 3H), 1.47 (d, J=6.6Hz, 6H)

Example 3244-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-2-one324

Following the procedures in Example 323,9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepineand piperazin-2-one were reacted to give 324. MS: (ESI+)=395.1. 1H NMR(400 MHz, DMSO) δ 8.55 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H),7.81 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.6 Hz, 1H),4.60-4.40 (m, 4H), 4.06 (s, J=8.0 Hz, 2H), 3.84-3.68 (m, 2H), 1.47 (d,J=6.6 Hz, 6H).

Example 3254-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-2-one325

A solution of9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine317 (55.0 mg, 0.166 mmol), piperazin-2-one (0.110 g, 1.10 mmol) andtriethylamine (0.275 mL, 1.97 mmol) in N-methylpyrrolidinone (3.00 mL,31.1 mmol) was heated at 150° C. for 2 d. The reaction was filtered thrucelite then rinsed with EtOAc. The filtrate was washed water and brine.The organic layer was dried Na2SO4, concentrated to give 325, analyzedby rHPLC. MS: (ESI+)=395.1. 1H NMR (400 MHz, DMSO) δ 8.55 (d, J=8.7 Hz,1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 6.70 (d, J=8.8 Hz, 1H),5.88 (dt, J=13.2, 6.6 Hz, 1H), 4.63-4.30 (m, 4H), 4.06 (d, J=8.0 Hz,2H), 3.81-3.63 (m, 2H), 1.47 (d, J=6.6 Hz, 6H).

Example 3274-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one327

Following the procedure for 203, was prepared by substituting2-fluoropyridin-3-ylboronic acid with 2-fluoropyridin-4-ylboronic acidto give10-(2-fluoropyridin-4-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.242 g, 24%, MS (ESI(+)): m/z 404.9 (M+H), which was treated with 10%aq. HCl to give 327 (0.141 g, 59%). 1H NMR (400 MHz, DMSO) δ 11.53 (s,1H), 8.72 (d, J=2.2, 1H), 7.93 (s, 1H), 7.67 (dd, J=8.5, 2.3, 1H), 7.49(d, J=6.9, 1H), 7.15 (d, J=8.6, 1H), 6.55 (s, 1H), 6.48 (d, J=6.2, 1H),5.70 (dt, J=13.2, 6.7, 1H), 4.56 (s, 4H), 2.26 (s, 3H), 1.49 (d, J=6.6,6H). MS (ESI(+)): m/z 403.1 (M+H).

Example 328(3R,4S)-4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-3-ol328

Step 1

4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (0.60 g, 1.22 mmol) was partially dissolved in drydiethyleneglycol dimethyl ether (14 mL) and a solution of borane/THFcomplex (1M in THF, 7.29 mL, 7.29 mmol) was added dropwise. Afterstirring briefly at room temperature, the mixture was allowed to standfor 16 h. The mixture was then cooled in ice, and water (1.1 mL), 2Msodium hydroxide (3.6 mL) and 35% hydrogen peroxide (0.94 mL, 8.98 mmol)were added dropwise in sequence. The mixture was heated at 50° C. for 8h, then cooled, diluted with water (approximately 30 mL) and extractedthree times with ethyl acetate. The combined organic extracts were dried(Na2SO4), filtered and concentrated in vacuo. The resultant residue wassubjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM)to giveracemic-trans-3-Hydroxy-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (0.46 g, 74%), containing approx. 20% of4-hydroxypiperidine isomer. LCMS RT=4.48, [M+H]+=509.

Step 2

Racemic-trans-3-Hydroxy-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (0.215 g, 0.42 mmol) was suspended in dry THF (10mL) and triphenylphosphine (0.22 g, 0.85 mmol) and chloroacetic acid (82mg, 0.85 mmol) were added. Diethyl azodicarboxylate (0.133 mL, 0.85mmol) was added dropwise and the mixture was stirred at room temperaturefor 24 h. The mixture was concentrated and the resultant residue wassubjected to flash chromatography (SiO2, gradient 0-10% methanol inDCM). The resultant impure material was dissolved in dry DCM (5 mL) andtriphenylphosphine, chloroacetic acid and diethyl azodicarboxylate wereadded (quantities as above). The mixture was stirred at room temperaturefor 16 hr, then concentrated in vacuo, the crude product was trituratedwith ether and the liquor was concentrated. The resultant residue wassubjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM)to give impureracemic-cis-3-(2-Chloro-acetoxy)-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (0.297 g), which was used in the subsequent stepwithout further purification. LCMS RT=4.61, [M+H]+=585/587.

Step 3

A solution of impureracemic-cis-3-(2-chloro-acetoxy)-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (0.297 g) in dioxane (5 mL) was stirred withaqueous sodium hydroxide (1M, 4.2 mL) at room temperature for 16 h,followed by heating at 50° C. for approx. 24 h. The cooled mixture wasextracted three times with ethyl acetate, the combined organic extractswere dried (Na2SO4), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0-5%methanol in DCM) to giveracemic-cis-3-Hydroxy-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (17 mg). LCMS RT=4.50, [M+H]+509

To a solution ofcis-racemic-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (17 mg, 0.36 mmol) in DCM (1 mL) and methanol (0.6mL) was added 4M HCl in dioxane (1.5 mL) slowly and the reaction mixturestirred at RT for 2.5 h before being concentrated in vacuo. Theresultant residue was triturated in diethyl ether to give racemiccis-4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-3-olwhich was resolved as the (3R,4S) enantiomer 328 as a white solid (10mg, 67%). MS RT2.47, [M+H]+=409. ¹H NMR (DMSO-d6) δ: 8.92 (1H, br, d),8.33 (1 H, d, J=8.30 Hz), 7.97 (1 H, s), 7.08 (1 H, d, J=8.36 Hz), 6.96(1 H, d, J=1.66 Hz), 5.79 (1 H, t, J=6.59 Hz), 4.50 (4 H, d, J=7.99 Hz),4.06 (1 H, s), 3.27 (2 H, m), 3.17 (2 H, m), 2.97 (2 H, d, J=14.58 Hz),2.32-2.27 (1H, m), 2.29 (3 H, s), 1.74 (1 H, d, J=13.43 Hz), 1.46 (6 H,d, J=6.59 Hz)

Example 3292-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide329

A suspension of2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (310 mg, 0.72 mmol) in DCM (6 mL) and TEA (0.3 mL, 2.16mmol) was sonicated and stirred before addingN,N-dimethyl-2-chloroacetamide (98 mg, 0.8 mmol) and TBAI (28 mg, 0.072mmol) and the reaction mixture stirred for 72 h at RT before beingconcentrated in vacuo. The resultant residue was partitioned betweenwater and DCM and the aqueous extracted five times with DCM, thecombined organic extracts dried (Na2SO4), filtered and concentrated invacuo. The resultant residue was subjected to flash chromatpgraphy(SiO2, gradient 0 to 10% methanol in DCM) then triturated in diethylether to give 329 as a white solid (129 mg, 38%). LCMS: RT=2.71 min,[M+H]+=478. 1H NMR 400 MHz (CDCl3) δ: 8.44 (1 H, d, J=8.30 Hz), 7.61 (1H, s), 7.04 (1 H, d, J=8.43 Hz), 6.91 (1 H, s), 5.91 (1 H, t, J=6.63Hz), 4.45 (4H, d, J=14.92 Hz), 3.39 (2 H, m), 3.11 (2 H, m), 3.10 (3 H,s), 2.99 (1 H, m), 2.98 (3 H, s), 2.54 (2 H, m), 2.41 (3 H, s), 1.90 (4H, s), 1.57 (6 H, d, J=6.65 Hz)

Example 330trans-racemic-2-(3-hydroxy-4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,2-dimethylpropanamide330

A mixture oftrans-racemic-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-olhydrochloride (199 mg, 0.46 mmol), 2-bromo-2-methyl-N-methylpropionamide (83 mg, 0.46 mmol), NaOH (2 mL, 50% aqueous solution), TBAB(16 mg, 0.05 mmol) and DCM (2.5 mL) was stirred vigorously at RT for 7.5h. The phases were separated and the aqueous layer extracted three timeswith 10% methanol in DCM, the combined organic extracts washed withbrine then dried (Na2SO4), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient0 to 10% methanol in DCM) to give 330 (84 mg, 37%). LCMS: RT=2.54 min,[M+H]+=494. 1 H NMR 400 MHz (CDCl3) δ: 8.44 (1 H, d, J=8.23 Hz), 7.87 (1H, s), 7.48 (1 H, s), 7.17 (1 H, br), 7.08 (1 H, m), 6.86 (1 H, s),6.03-6.01 (1 H, m), 4.77-4.07 (4 H, m), 3.82 (1 H, br), 3.17 (1 H, m),2.86 (3 H, d, J=4.98 Hz), 2.85 (2H, m), 2.46 (1 H, m), 2.27 (1 H, m),2.18 (1 H, m), 1.90 (1 H, m), 1.70 (1 H, m), 1.61 (6 H, m), 1.27 (6 H,d, J=10.69 Hz)

Example 3312-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)-N,N-dimethylacetamide331

A solution of9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine317 (80.0 mg, 0.242 mmol), ethyl 2-(piperazin-1-yl)acetate (0.275 g,1.60 mmol) and Triethylamine (0.400 mL, 2.87 mmol) inN-Methylpyrrolidinone (4.36 mL, 45.2 mmol) was heated at 150° C. for 2days. The reaction was filtered thru celite then rinsed with EtOAc. Thefiltrate was washed water, brine. The organic layer was dried Na2SO4,concentrated. To a solution of crude ethy ester intermediate inTetrahydrofuran (3.00 mL, 37.0 mmol) and Water (3.00 mL, 166 mmol) wasadded Lithium hydroxide hydrate (0.0406 g, 0.967 mmol;). The reactionwas stirred at r.t. The reaction was quenched with water then washEtOAc. The aqueous layer was concentrated to give2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)aceticacid which was carried to next reaction. MS: (ESI+)=439.2

2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)aceticacid (0.050 g, 0.00011 mol;) dissolved in N,N-Dimethylformamide (1.79mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine(0.119 mL, 0.000686 mol) Dimethylamine hydrochloride (0.0373 g, 0.000457mol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate (0.0521 g, 0.000137 mol). Stir at r.t. 2 h. Add sat.sodium bicarbonate, extract with ethyl acetate. Dry organics over sodiumsulfate and concentrate to give 331, analyzed by rHPLC. MS:(ESI+)=466.2. 1H NMR (400 MHz, DMSO) δ 9.10 (s, 1H), 7.89 (s, 1H), 7.84(s, 1H), 6.34 (s, 1H), 6.01-5.79 (m, 1H), 4.50 (d, J=10.0 Hz, 4H), 3.53(s, 4H), 3.18 (s, 2H), 3.03 (s, 3H), 2.82 (s, 3H), 1.47 (d, J=6.5 Hz,6H).

Example 3322-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetamide332

2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)aceticacid from Example 331 (0.050 g, 0.11 mmol) dissolved inN,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentiallywith N,N-Diisopropylethylamine (0.119 mL, 0.686 mmol) Ammonium chloride(0.0244 g, 0.457 mmol) thenN,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate (0.0521 g, 0.137 mmol;). Stir at r.t. 2 h. Add sat.sodium bicarbonate, extract with ethyl acetate. Dry organics over sodiumsulfate and concentrate to give 332, analyzed by rHPLC. MS:(ESI+)=466.2. 1H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 7.89 (s, 1H), 7.85(s, 1H), 7.20 (s, 2H), 6.35 (s, 1H), 5.93 (dt, J=13.7, 7.0 Hz, 1H), 4.50(d, J=10.4 Hz, 4H), 3.57 (s, 5H), 2.91 (s, 2H), 1.47 (d, J=6.5 Hz, 6H).

Example 3332-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9(8H)-one333

A solution of9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine-2-carboxamide(55.0 mg, 0.166 mmol) in Sulfuric acid (0.70 mL, 13 mmol) and Water(0.70 mL, 39 mmol) was heated at 125 C for 2 h. The reaction was dilutedwith water, neutralized 1M NaOH then extracted EtOAc. The organic layerwas dried Na2SO4, concentrated to give 333 after rHPLC purification. MS:(ESI+)=313.0

Example 3342-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)-N-methylacetamide334

A solution of9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine(150.0 mg, 0.4535 mmol), ethyl 2-(piperazin-1-yl)acetate (0.275 g, 1.60mmol) and Triethylamine (0.400 mL, 2.87 mmol) in N-Methylpyrrolidinone(4.36 mL, 45.2 mmol) was heated at 150 C for 2 d. The reaction wasdiluted with EtOAc then wash with water and brine. The organic layer wasdried Na2SO4, concentrated to give intermediate ethyl ester which wasdissolved in Tetrahydrofuran (8.00 mL, 98.6 mmol) and Water (8.00 mL,444 mmol). Lithium hydroxide hydrate (0.07612 g, 1.814 mmol) was added.The reaction was stirred at room temp. and then quenched with water andwashed with EtOAc. The aqueous layer was concentrated to give2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)aceticacid. MS: (ESI+)=439.4

2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)aceticacid (0.050 g, 0.00011 mol) was dissolved in N,N-Dimethylformamide (1.79mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine(0.119 mL, 0.000686 mol) 2.00 M of Methylamine in Tetrahydrofuran (0.228mL) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate (0.0521 g, 0.000137 mol). Stir at r.t. 2 h. Add sat.sodium bicarbonate, extract with ethyl acetate. Dry organics over sodiumsulfate and concentrate to give 334, analyzed by rHPLC. MS: (ESI+)=452.2

Example 3352-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)-N,N-dimethylacetamide335

2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)aceticacid from Example 334 (0.050 g, 0.00011 mol) dissolved inN,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentiallywith N,N-Diisopropylethylamine (0.119 mL, 0.000686 mol) Dimethylaminehydrochloride (0.0373 g, 0.000457 mol) thenN,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate (0.0521 g, 0.137 mmol). Stir at r.t. 2 h. Add sat.sodium bicarbonate, extract with ethyl acetate. Dry organics over sodiumsulfate and concentrated to give 335, analyzed by rHPLC. MS:(ESI+)=466.3

Example 3362-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)aceticacid 336 Step 1: methyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate

Following the procedures of Example 300,9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 and 1-(tert-butyldimethylsilyloxy)-1-methoxyethene were reacted togive methyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate.M/z 368.2, calc. 367.16

Step 2

ethyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetateand lithium hydroxide were reacted to give 336. M/z 354.1, calc. 353.15

Example 3371-((2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methyl)urea337

Methyl2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate(0.6 g, 2.0 mmol), prepared according to Example 40,1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.477 mmol, 2.02 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.059 g, 0.084 mmol) were combined in a 35-mL microwaveablevessel. Subsequently, potassium carbonate (1.0 M in water, 5 mL) andacetonitrile (5 mL) were added. The reaction vessel was then subjectedto microwave irradiation at 140° C. for 20 min. The mixture was dilutedfurther with EtOAc and the product was isolated via acid-base extractionto provide 0.3 g (50% yield) of2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid.

2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (0.3 g, 0.9 mmol) was dissolved in tetrahydrofuran (3 mL) andammonium chloride (0.19 g, 3.6 mmol) and N,N-diisopropylethylamine (0.31mL, 1.8 mmol) were added followed byN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uraniumhexafluorophosphate (HATU) (0.37 g, 0.98 mmol) lastly and the resultingmixture was stirred at ambient temperature for 2 h. The reaction wascomplete as indicated by LCMS analysis. The reaction mixture was thendiluted with saturated aqueous sodium bicarbonate solution and extractedwith EtOAc twice. The combined organic layers were washed once withbrine and dried over Na2SO4. The liquid was filtered and concentrated todryness. The crude residue was carried on to the subsequent reactionwithout further purification steps applied. This provided 0.3 g(quantitative) of2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide.MS (ESI+) m/z 338.1 (M+H+), calcd. 338.4

Lithium tetrahydroaluminate (0.047 g, 1.3 mmol) was suspended intetrahydrofuran (8 mL) and cooled to 0° C. A solution of2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide(0.3 g, 0.9 mmol) in tetrahydrofuran (2 mL) was added and the reactionmixture was stirred at cold temperature for 10 min. The flask wasgradually brought to room temperature and stirred for 16 h. The reactionwas quenched by pouring into a mixture of diethyl ether and saturatedaqueous Rochelle's salt solution (1:1). The mixture containingsignificant emulsion was stirred very vigorously until the phasesseparated (ca. 2 h). The phases were partitioned and the aqueous layerwas extracted numerous times with EtOAc. The combined organic layerswere dried over MgSO4, filtered and concentrated to give (0.15 g, 0.46mmol)(2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methanamine(MS (ESI+) m/z 323.1 (M+H+), calcd. 323.4) which was dissolved inglacial acetic acid (0.8 mL) and water (5 mL). A solution of potassiumcyanate (0.114 g, 1.41 mmol) in water was added dropwise.N,N-dimethylformamide (3 mL) was added to help with dissolution. Theresulting reaction mixture was stirred at room temperature for 12 h.Subsequently, the reaction was heated at 50° C. for 3 h. The mixture wascooled to room temperature and filtered to provide 0.02 g (10% yield) of337. MS (ESI+) m/z 367.1 (M+H+), calcd. 367.4. 1H NMR (400 MHz, DMSO) δ8.53 (s, 5H), 8.33 (d, J=8.2 Hz, 1H), 7.61 (d, J=3.7 Hz, 1H), 7.43 (s,1H), 7.01 (d, J=8.7 Hz, 1H), 6.91 (s, 1H), 6.63 (s, 1H), 6.38 (s, 1H),5.62 (s, 2H), 5.42 (s, 7H), 4.47 (s, 3H), 4.17 (d, J=5.8 Hz, 2H), 1.44(d, J=6.4 Hz, 6H)

Example 338(2S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide338

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and L-prolinamide, were reacted and the crude productsubjected to flash chromatography (SiO2, gradient 0 to 8% methanol inDCM) then recrystallisation from methanol to give 338 as a white solid(115 mg, 44%). LCMS: RT=2.48 min, [M+H]+409. ¹H NMR 400 MHz (DMSO-d6) δ:9.06 (1 H, s), 7.88 (1 H, s), 7.83 (1 H, s), 7.33 (1 H, br), 6.92 (1 H,br), 5.97-5.96 (1 H, m), 5.94 (1 H, s), 4.53-4.45 (4 H, m), 4.30 (1 H,d, J=8.51 Hz), 3.59 (1 H, s), 3.37 (1 H, d, J=9.93 Hz), 2.18 (1 H, m),1.95 (3 H, m), 1.47 (6 H, dd, J=6.59, 3.43 Hz)

Example 3391-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperidine-4-carboxamide339

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 was treated with sodium hydride, (1.2 eq.) and thereaction mixture stirred at RT or 40 C for 15 min to 1.25 h before theaddition of benzenebis(trifluoromethane) sulfonamide (1.2 eq.). Stirringwas continued at RT until complete consumption of pyridone was seen (TLCor LCMS) then piperidine-4-carboxylic acid amide was added (1 to 2.5eq.) and the reaction mixture heated at 70 to 100 C until no furtherreaction was seen. The crude products were isolated by removal ofsolvent in vacuo, precipitation from the reaction mixture by addition ofwater, addition of water and extraction with ethyl acetate or DCM, or byusing an Isolute SCX-2 cartridge and the crude product recrystallisedfrom methanol to give 339 as a white solid (161 mg, 60%). LCMS: RT=2.41min, [M+H]+423. ¹ H NMR 400 MHz (DMSO-d6) δ: 9.10 (1 H, s), 7.88 (1 H,d, J=0.65 Hz), 7.83 (1 H, s), 7.27 (1 H, s), 6.76 (1 H, s), 6.34 (1 H,s), 5.93-5.92 (1 H, m), 4.51-4.49 (4 H, m), 4.31 (2 H, d, J=13.19 Hz),2.94-2.81 (2 H, m), 2.38-2.35 (1 H, m), 1.73 (2 H, m), 1.53 (2 H, dd,J=12.25, 3.87 Hz), 1.47 (6 H, d, J=6.60 Hz)

Example 3401-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperidin-4-ol340

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 4-hydroxypiperidine, the crude product wasrecrystallised from methanol to give 340 as a white solid (106 mg, 42%).LCMS: RT=2.48 min, [M+H]+=396. ¹ H NMR 400 MHz (DMSO-d6) δ: 9.09 (1 H,s), 7.88 (1 H, d, J=0.64 Hz), 7.83 (1 H, s), 6.33 (1 H, s), 5.97-5.88 (1H, m), 4.69 (1 H, d, J=4.26 Hz), 4.49-4.48 (4 H, m), 4.03-3.99 (2 H, m),3.75-3.67 (1 H, m), 3.14-3.13 (2 H, m), 1.80-1.71 (2 H, m), 1.47 (6 H,d, J=6.60 Hz), 1.34-1.33 (2 H, m)

Example 3412-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-morpholino-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine341

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and morpholine, the crude product was recrystallisedfrom methanol to give 341 as a white solid (107 mg, 44%). LCMS: RT=3.12min, [M+H]+382. ¹H NMR 400 MHz (DMSO-d) δ: 9.14 (1 H, s), 7.90 (1 H, d,J=0.63 Hz), 7.86 (1 H, s), 6.36 (1 H, s), 5.93-5.92 (1 H, m), 4.57-4.48(4 H, m), 3.70 (4 H, t, J=4.74 Hz), 3.50 (4 H, t, J=4.74 Hz), 1.49 (6 H,d, J=6.60 Hz)

Example 342N-isopropyl-2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetamide342

Following the procedures of Example 331, 342 was prepared. MS:(ESI+)=480.2

Example 3431-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)azetidine-3-carboxamide343

A solution of9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine-2-carboxamide(45.0 mg, 0.136 mmol), azetidine-3-carboxylic acid (30.0 mg, 0.297 mmol)and Triethylamine (0.300 mL, 2.15 mmol) in Isopropyl alcohol (1.00 mL,13.1 mmol) was heated at 150 C for 2 days. The reaction was diluted withwater then washed with EtOAc. The aqueous layer was acidified thenextracted with EtOAc. The organic layer was dried Na2SO4, concentratedto give carboxylic acid intermediate,1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)azetidine-3-carboxylicacid (MS: (ESI+) 396.1) which was dissolved (0.060 g, 0.00015 mol) inN,N-Dimethylformamide (2.37 mL, 0.0306 mol) and treated sequentiallywith N,N-Diisopropylethylamine (0.158 mL, 0.000910 mol) Ammoniumchloride (0.0325 g, 0.607 mmol) thenN,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate (HATU, 0.0692 g, 0.000182 mol). Stirred at RT2 hr.Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organicsover sodium sulfate and concentrated to give 343, analyzed by rHPLC. MS:(ESI+)=395.1. 1H NMR (400 MHz, DMSO) δ 8.50 (d, J=8.5 Hz, 1H), 7.88 (s,1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.04 (s, 1H), 6.28 (d, J=8.5 Hz, 1H),5.96-5.76 (m, 1H), 4.48 (d, J=10.2 Hz, 4H), 4.09 (t, J=8.3 Hz, 2H), 3.98(t, J=6.9 Hz, 2H), 3.44 (dd, J=14.5, 7.4 Hz, 1H), 1.46 (d, J=6.5 Hz,6H).

Examples 344 and 345(2S)-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanamide344 and(2R)-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanamide345

A degassed mixture of 187 mg (0.500 mmol) of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194, 320.6 mg (2.000 mmol) of (1-trimethylsilyloxy)-1-methoxyprop-1-ene,19.4 mg (0.025 mmol) of bromo(tri-t-butylphosphine)palladium dimer and154.5 mg (0.500 mmol) of tributyltin fluoride in 4.0 ml of 1,4-dioxanewas heated for 18 hours at 105° C. After a work up a mixture ofsaturated and unsaturated esters was separated from a product ofdebromination by column chromatography eluting with 1-4% gradient ofmethanol in dichloromethane. 98 mg of the above mixture and 100 mg of10% Pd-Carbon in 12 ml of ethanol was hydrogenated at 1 atm for 3 hours.The mixture was filtered, the filtrate concentrated in vacuum giving 80mg of pure methyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoate.M/z 382.1, calc. 381.18

Methyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoateand lithium hydroxide were reacted to give2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoicacid. M/z 368.2, calc. 367.16, which was reacted with ammonium chlorideand HATU following the procedure of Example 215 to give a racemicmixture of enantiomers 344 and 345. M/z 367.1, calc. 366.18. 1H NMR (400MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 7.90 (s, 2H), 7.41 (s, 1H), 7.10 (d,J=8.5, 1H), 7.00 (s, 1H), 6.87 (s, 1H), 5.88 (dt, J=12.5, 6.2, 1H), 4.50(d, J=4.7, 4H), 3.57 (q, J=6.9, 1H), 1.48 (d, J=6.5, 6H), 1.31 (d,J=6.9, 3H)

Example 3482-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(oxetan-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine348

Generation of boronic acid: A solution of2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(Example 57, 0.495 g, 0.00114 mol) and Sodium periodate (0.730 g,0.00341 mol) in a 4:1 mixture of Tetrahydrofuran (7.38 mL) and Water(1.84 m) was stirred at room temperature for 30 minutes. AqueousHydrogen chloride (0.000796 mol, 1N, 0.8 mL) was added and the reactionwas stirred at room temperature overnight. The mixture was diluted withwater and extracted 3 times with methylene chloride. The organic layerswere combined, dried with MgSO4 and concentrated. The crude material wascarried forward without further purification.

To a CEM microwave vial was added the crude boronic acid (0.154 g, 0.437mmol), Nickel(II)iodide (0.0186 g, 0.0596 mmol),trans-2-Aminocyclohexanol hydrochloride (0.00904 g, 0.0596 mmol) andSodium hexamethyldisilazane (0.477 mmol, 2M in THF, 0.24 mL), indegassed Isopropyl alcohol (0.91 mL) and Dimethyl sulfoxide (1.5 mL).The mixture was continuously purged with nitrogen. 3-iodooxetane (0.0731g, 0.398 mmol) in Isopropyl alcohol (0.21 mL) was added and the vial wascapped immediately. The reaction was heated to 85° C. in the microwavefor 25 minutes. About 50% conversion to product was observed byLC/MS-protodeboronation was also observed. The mixture was diluted withmethylene chloride and filtered through celite. Water was added and themixture was extracted 3 times with methylene chloride. The crude wasloaded as a solid onto silica gel and purified by flash chromatography(50% EtOAc in hexanes), and re-purified by reverse-phase HPLC to give25.8 mg of 348 as a white solid. MS(ESI+) 366.1. 1H NMR (400 MHz, DMSO)δ 8.40 (d, J=8.2 Hz, 1H), 7.89 (s, 1H), 7.22 (d, J=8.3 Hz, 1H), 7.06 (s,1H), 5.93-5.73 (m, 1H), 4.94 (t, J=7.0 Hz, 2H), 4.63 (t, J=6.2 Hz, 2H),4.55-4.46 (m, 4H), 4.33-4.18 (m, 1H), 2.25 (s, 3H), 1.46 (d, J=6.4 Hz,6H)

Example 3512-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetamide351

Following the procedures of Example 215,2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)aceticacid, ammonium chloride, and HATU were reacted to give 351. M/z 353.1,calc. 352.16. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 7.91 (s,2H), 7.48 (s, 1H), 7.04 (d, J=8.2, 1H), 6.97 (s, 1H), 6.92 (s, 1H),5.95-5.81 (m, 1H), 4.50 (d, J=5.8, 4H), 3.38 (s, 2H), 1.48 (d, J=6.5,6H)

Example 352N-hydroxy-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetamide352

Following the procedures of Example 316,2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)aceticacid and hydroxylamine were reacted to give 352. M/z 369.1, calc.368.16. 1H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 8.88 (s, 1H), 8.32 (d,J=8.2, 1H), 7.92 (d, J=2.9, 2H), 7.04 (d, J=8.2, 1H), 6.97 (s, 1H),5.95-5.81 (m, 1H), 4.50 (d, J=5.7, 4H), 3.29 (s, 2H), 1.48 (d, J=6.6,6H)

Example 353(9-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)(S-dioxothiomorpholino)methanone353

Following the procedures in the Examples herein, amide coupling andSuzuki coupling gave 353. MS(ESI+): 486.1

Example 3541-((2-(1-(2,4-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methyl)urea354

C-{2-[2-(2,4-Difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-methylaminein acetic acid and water was reacted with potassium cyanate in water togive 354. MS(ESI+) 452.1. 1H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.68(td, J=8.7, 6.2 Hz, 1H), 7.62-7.54 (m, 2H), 7.32-7.25 (m, 1H), 6.87-6.80(m, 2H), 6.44 (t, J=6.1 Hz, 1H), 5.57 (br, 2H), 4.49-4.38 (m, 4H), 4.12(d, J=6.1 Hz, 2H), 2.35 (s, 3H)

Example 355(2-(1-(2,4-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methanamine355

To a solution of8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acidamide (5.00 g, 0.0162 mol) in Toluene (85 mL) was addedDimethylacetamide-dimethylacetal (7.23 mL, 0.0487 mol). The reaction wasstirred at 95° C. for 4 h. The toluene was removed in vacuo and thecrude 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylicacid [1-dimethylamino-eth-(E)-ylidene]-amide was carried forward withoutfurther purification. MS(ESI+) 377.1/379.1

8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid[1-dimethylamino-eth-(E)-ylidene]-amide (0.0162 mol) was dissolved inAcetic acid (50 mL). 2,4-Difluorophenylhydrazine hydrochloride (3.52 g,0.0195 mol) was added and the reaction was stirred at 95° C. overnight.The acetic acid was removed in vacuo. The crude was loaded as a solidonto silica gel and purified by flash chromatography (4-10% methanol inmethylene chloride) to afford 3.662 g8-Bromo-2-[2-(2,4-difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneas an orange solid. MS(ESI+) 458.0/460.0

8-Bromo-2-[2-(2,4-difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas reacted with zinc cyanide, andTetrakis(triphenylphosphine)palladium(0) in DMF under microwaveirradiation at 60 W for 30 minutes (Tmax=175° C.) to give2-[2-(2,4-difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbonitrile.MS(ESI+) 405.1

To2-[2-(2,4-Difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbonitrilein tetrahydrofuran was added Lithium tetrahydroaluminate (1M in THF),dropwise at 0° C. The reaction was stirred for 2 hours and quenched withsaturated Na2SO4 until H2 evolution ceased. MgSO4 was added and thewhole was diluted with copious amounts of methylene chloride, filteredover celite, and concentrated in vacuo. The crude was purified by flashchromatography (1-15% MeOH in DCM spiked with Et3N) to afford to give355. MS(ESI+) 409.1. 1H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.68 (td,J=8.7, 6.2 Hz, 1H), 7.64-7.52 (m, 2H), 7.32-7.25 (m, 1H), 6.95 (s, 1H),6.91 (dd, J=8.2, 1.2 Hz, 1H), 4.48-4.38 (m, 4H), 3.66 (s, 2H), 2.35 (s,3H).

Example 3569-(1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)-N-(2-hydroxyethyl)-N-isopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide356

Step 1

A sealed flask containing8-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (500 mg,1.28 mmol), palladium (II) chloride (6 mg, 0.03 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15 mg, 0.03 mmol) wasflushed with CO. 2-Isopropylamino ethanol (172 mg, 1.67 mmol), and TEA(0.53 mL, 3.8 mmol) were added as a solution in toluene (2.5 mL) and thereaction mixture heated at 100° C. for 3.5 h. The reaction mixture waswashed with water and extracted with ethyl acetate (2×30 mL). Thecombined organic extracts were washed with brine, dried (Na2SO4) andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 2-3% methanol in DCM) to yield8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (123 mg, 23%). LCMS: RT=3.11 min,[M+H]+=394/396

Step 2

8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (114 mg, 0.28 mmol),3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (129 mg,0.62 mmol), potassium carbonate (96 mg, 0.69 mmol) and PdCl2dppf.DCM (20mg, 0.02 mmol) were suspended in DMF (1.5 mL), and the reaction mixturepurged with argon. The reaction mixture was heated at 100° C. for 3 h.The reaction mixture was washed with water, extracted with ethyl acetate(2×15 mL) and the combined organic extracts washed with brine, dried(Na2SO4) and concentrated in vacuo. The resultant residue was subjectedto flash chromatography (SiO2, gradient 0-2% MeOH in DCM) to yield4-{2-[(2-Hydroxy-ethyl)-isopropyl-carbamoyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (115 mg, 80%). LCMS: RT=3.48 min, [M+H]+=497

Step 38-Piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide hydrochloride

To a solution of4-{2-[(2-hydroxy-ethyl)-isopropyl-carbamoyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (112 mg, 0.23 mmol) in IMS (3 mL) was addedhydrochloric acid (2 mL, 2M, 4.0 mmol) and palladium on carbon (20 mg,10% by wt) added. The reaction mixture was stirred under an atmosphereof hydrogen at 50° C. for 4.5 h. The reaction mixture was filtered andthe solids washed with IMS (10 mL). The filtrate was concentrated invacuo and azeotroped with acetonitrile to yield8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide hydrochloride as a thick oil (110mg). LCMS: RT=0.32 min, [M+H]+=399

To a stirred mixture of8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide hydrochloride (127 mg, 0.23 mmol)in DMF (2 mL) was added potassium carbonate (127 mg, 0.92 mmol),N,N-dimethyl-2-chloroacetamide (36 mg, 0.3 mmol) and KI (catalytic) andstirring continued at RT for 72 h before concentrating in vacuo. Theresultant residue was diluted with ethyl acetate and washed with waterfollowed by brine, then dried (Na2SO4), filtered and concentrated invacuo. The resultant residue was passed down an Isolute SCX-2 cartridgeeluting with DCM/methanol then 2M NH3 in methanol. Basic fractions werecombined and concentrated in vacuo, the residue subjected to RPHPLC (C18column, gradient 5 to 95% CH3CN in water+0.1% HCO2H) to give 356 as acolourless glass (22 mg, 20%). LCMS: RT=1.90 min, [M+H]+=484 1H NMR 400MHz (CDCl3) δ: 8.42 (2 H, s), 8.20 (1H, br, s), 8.34 (1 H, d, J=8.32Hz), 7.81 (1 H, s), 7.04 (1 H, dd, J=8.40, 1.77 Hz), 6.90 (1 H, d,J=1.69 Hz), 4.63 (2 H, m), 4.45-4.44 (4 H, m), 3.38 (3 H, m), 3.32 (2 H,m), 3.16 (2 H, d, J=11.21 Hz), 3.11 (3 H, s), 2.99 (3 H, s), 2.56 (1 H,m), 2.48 (2 H, m), 1.87 (4 H, m), 1.42 (6 H, d, J=6.46 Hz)

Example 3572-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-isopropylpiperidin-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine357

A suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoro acetate (250 mg, 0.51 mmol) in DCE (5 mL) was added acetone(0.06 mL, 0.77 mmol) and 4 Å molecular sieves was stirred under anatmosphere of argon for 10 min before adding sodium triacetoxyborohydride (216 mg, 1.02 mmol) and stirring for 18 h at RT. Furtheracetone (0.06 mL) and sodium triacetoxyborohydride (216 mg) were addedand stirring continued for a further 24 h. The reaction mixture wasdiluted with DCM and saturated aqueous sodium hydrogen carbonate and theorganic layer washed with water followed by brine and then dried(MgSO4), filtered and concentrated in vacuo. The resultant solid wassubjected to RPHPLC (gradient 20 to 70% methanol in water+0.1% HCO2H) togive 357 as a yellow solid (17 mg, 8%). LCMS: RT=2.81 min, [M+H]+=421.¹H NMR 400 MHz (DMSO-d) δ: 8.37-8.26 (1 H, m), 7.90-7.89 (2 H, m), 7.05(1 H, dd, J=8.33, 1.81 Hz), 6.89 (1 H, d, J=1.73 Hz), 5.89-5.88 (1 H,m), 4.49-4.48 (4 H, m), 2.91 (2 H, d, J=10.95 Hz), 2.76-2.75 (1 H, m),2.46 (1 H, s), 2.26 (2 H, t, J=11.38 Hz), 1.78 (2 H, d, J=12.43 Hz),1.64 (2 H, td, J=12.20, 3.68 Hz), 1.48 (6 H, d, J=6.60 Hz), 1.01 (6 H,d, J=6.57 Hz)

Example 3582-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropan-1-ol358

A mixture of2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenehydrochloride (100 mg, 0.255 mmol), 2-bromo-2-methyl-propionic acidethyl ester (45 uL, 0.31 mmol), cesium carbonate (187 mg, 0.57 mmol) andDMF (0.5 mL) was heated at 70° C. for 3 h the then stirred at RT for 18h then heated again at 70° C. for 4 h before concentrating in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient0 to 5% methanol in DCM) to give2-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionicacid ethyl ester (47 mg, 36%). LCMS RT=2.24, [M+H]+=507.

A solution of2-{4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionicacid ethyl ester (47 mg, 0.092 mmol) in anhydrous THF (3 mL) was cooledto 0° C. and treated with lithium aluminium hydride (1M solution in THF,0.3 mL, 0.3 mmol), the mixture stirred and allowed to warm to RT beforequenching by the addition of saturated aqueous sodium hydrogencarbonate. The resultant mixture was extracted twice with ethyl acetate,the combined organic extracts dried (Na2SO4), filtered and concentratedin vacuo. The resultant residue was subjected to RPHPLC (C18 column,gradient 0 to 60% methanol in water+0.1% formic acid) to give 358 as awhite solid (20 mg, 47%). LCMS: RT=2.74 min, [M+H]+=465. ¹H NMR 400 MHz(DMSO-d) δ: 8.33 (1 H, d, J=8.28 Hz), 8.26 (1 H, s), 7.87 (1 H, s), 7.05(1 H, dd, J=8.35, 1.77 Hz), 6.90 (1 H, d, J=1.71 Hz), 5.82-5.81 (1 H,m), 4.49 (4 H, m), 3.38 (2 H, s), 3.21 (2 H, d, J=11.33 Hz), 2.58 (1 H,t, J=11.87 Hz), 2.47 (2 H, d, J=11.47 Hz), 2.26 (3 H, s), 1.85 (2 H, d,J=12.54 Hz), 1.72 (2 H, m), 1.46 (6 H, d, J=6.60 Hz), 1.07 (6 H, s)

Example 3592-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropan-1-ol359

Following the procedures of Example 358,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoro acetate (103 mg) was converted to 359, a white solid (6.6 mg,2% overall yield). LCMS: RT=2.73 min, [M+H]+=451. ¹H NMR 400 MHz(DMSO-d) δ: 8.33 (1 H, d, J=8.28 Hz), 7.91 (2 H, d, J=2.06 Hz), 7.06 (1H, dd, J=8.35, 1.76 Hz), 6.90 (1 H, d, J=1.71 Hz), 5.90 (1 H, t, J=6.60Hz), 4.50 (4 H, dd, J=11.70, 5.85 Hz), 3.34 (2 H, br, m), 3.13 (2 H, d,J=11.26 Hz), 2.55 (1H, m), 2.35 (2 H, t, J=11.38 Hz), 1.81 (2 H, d,J=12.50 Hz), 1.64 (2 H, d, J=12.44 Hz), 1.49 (6 H, d, J=6.60 Hz), 1.02(6 H, s)

Example 3604-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrazolidine-3,5-dione360

A mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 (1410 mg (3.77 mmol), diethyl malonate (2.00 mL (13.2 mmol),palladium (II) acetate (42.3 mg, 0.188 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (148 mg, 0.377mmol) and potassium phosphate (2.80 g, 13.2 mmol) in 6.0 ml of1,4-Dioxane was degassed and heated for 24 hours at 100° C. The mixturewas concentrated in vacuum and the residue purified on 24 g silicacolumn eluting with 1% of MeOH in EtOAc to give diethyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)malonate.Yield 974 mg. M/z 454.3, calc. 453.20

A mixture of 181 mg (0.40 mmol) of diethyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)malonateand 0.314 mL (10.0 mmol) of hydrazine in 4.0 ml of Ethanol was heated at75° C. for 18 hours. The mixture was concentrated, the residuetriturated with acetic acid. A precipitate was filtered off, washed withacetic acid, ethyl ether and recrystallized from ethyl ether/ethanolmixture to give 360. Yield 59 mg (37.5%). M/z 394.1, calc. 393.15. 1HNMR (400 MHz, DMSO) δ 10.20 (s, 2H), 8.29 (d, J=8.6, 1H), 7.89 (d,J=12.9, 2H), 7.70 (d, J=8.5, 1H), 7.63 (s, 1H), 5.93 (dt, J=13.1, 6.7,1H), 4.48 (d, J=7.2, 4H), 1.49 (d, J=6.6, 6H)

Example 3612-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine361

A suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenetrifluoro acetate (250 mg, 0.51 mmol) in THF (5 mL) was treated with TEAand the mixture flushed with argon. 2,2,2-trifluoroethyltrifluoromethane sulfonate (0.15 mL, 1.02 mmol) was added and themixture stirred at RT for 72 h. The reaction mixture was partitionedbetween DCM and water, the organic layer washed with saturated aqueoussodium hydrogen carbonate followed by brine and then dried (MgSO4),filtered and concentrated in vacuo. The resultant residue was dissolvedin 1.25 M HCl in methanol then concentrated in vacuo to give a solidwhich was triturated in IPA then diethyl ether. The resultant solid wassubjected to RPHPLC (C18 column, gradient 10 to 98% methanol inwater+0.1% HCO2H) to give 361 as a white solid (49 mg, 23%). LCMS:RT=4.59 min, [M+H]+=461. ¹H NMR 400 MHz (DMSO-d6) δ: 8.33 (1 H, d,J=8.29 Hz), 7.91-7.91 (2 H, m), 7.08 (1 H, dd, J=8.36, 1.79 Hz), 6.92 (1H, m), 5.91-5.90 (1 H, m), 4.51 (4 H, q, J=5.90 Hz), 3.21 (2 H, q,J=10.30 Hz), 3.03 (2 H, d, J=11.25 Hz), 2.45 (3 H, m), 1.76 (2 H, m),1.69-1.67 (2 H, m), 1.49 (6 H, d, J=6.60 Hz)

Example 3631-((2-(1-(2,4-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methylamino)-2-methylpropan-2-ol363

To a slurry ofC-{2-[2-(2,4-Difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-methylamine(0.150 g, 0.000367 mol) and Cesium Carbonate (0.0335 g, 0.000103 mol) inMethanol (0.5 mL) was added Isobutylene Oxide (0.0359 mL, 0.000404 mol).The flask was sealed and heated to 70° C. for 2 hours.

The mixture was diluted with diethyl ether and water was added. Themixture was extracted 3 times with diethyl ether. The organic phaseswere combined, dried with MgSO4 and concentrated to give 11.2 mg of 363as a white solid (6.4% yield). MS(ESI+) 481.2. 1H NMR (400 MHz, DMSO) δ7.89 (s, 1H), 7.68 (td, J=8.6, 6.0 Hz, 1H), 7.63-7.51 (m, 2H), 7.29 (td,J=8.2, 1.5 Hz, 1H), 6.94 (s, 1H), 6.90 (dd, J=8.3, 1.3 Hz, 1H),4.47-4.38 (m, 4H), 4.20 (s, 1H), 3.67 (s, 2H), 2.35 (s, 3H), 2.33 (s,2H), 1.08 (s, 6H)

Example 3642-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine364

A solution of9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine317 (35.0 mg, 0.106 mmol) in Methanol (1.91 mL, 47.1 mmol) was addedTriethylamine (0.0147 mL, 0.106 mmol) and Palladium (0.0113 g, 0.0106mmol). The reaction was stirred overnight at room temperature under H2atm. The reaction was filtered thru celite. The solute was concentratedthen diluted with EtOAc, wash with H2O. The organic layer was driedNa2SO4, concentrated. The crude product was purified by isco column togive 364. MS: (ESI+)=297.1. 1H NMR (400 MHz, DMSO) δ 9.49 (s, 1H), 8.36(d, J=5.7 Hz, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.05 (d, J=5.7 Hz, 1H),5.90 (dt, J=13.2, 6.5 Hz, 1H), 4.59 (dt, J=26.2, 13.1 Hz, 4H), 1.50 (d,J=6.6 Hz, 6H)

Example 365(2R)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide365

A solution of9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine317 (25.0 mg, 0.0756 mmol), R-Prolinamide (0.0570 g, 0.499 mmol) andTriethylamine (0.125 mL, 0.897 mmol) in N-Methylpyrrolidinone (1.36 mL,14.1 mmol) was heated at 150 C for 2 d. The reaction was filtered thrucelite then rinsed with EtOAc. The filtrate was washed water, brine. Theorganic layer was dried Na2SO4, concentrated to give 365, analyzed byrHPLC. MS: (ESI+) 409.2

Example 3662-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(pyrrolidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine366

Following the procedures for Example 365, 366 was prepared. MS:(ESI+)=366.2. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 7.88 (s, 1H), 7.82(s, 1H), 5.94 (dd, J=13.6, 6.9 Hz, 1H), 4.61-4.32 (m, 4H), 3.40 (d,J=6.3 Hz, 4H), 1.95 (t, J=6.5 Hz, 4H), 1.48 (d, J=6.6 Hz, 6H)

Example 3672-(1-isopropyl-1H-1,2,4-triazol-5-yl)-N-methyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-amine367

A mixture of 1.936 g (11.00 mmol) of 2,6-dichloronicotinaldehyde, 6.384g (44.00 mmol) of aqueous ethanedial and aqueous Ammonia (4.996 g, 88.00mmol) in 60 ml of methanol was stirred for 3 hours. The mixture wasconcentrated in vacuum and acidified to pH<1 with 200 ml of 0.5 N aqHCl. The aqueous solution was extracted with ethyl acetate (3×30 ml).The organic extracts were discarded while aqueous was basified byaddition of sat NaHCO3. The mixture was extracted with ethyl acetate(3×30 ml), combined organic extracts were washed with water, brine,dried and concentrated in vacuum to give2,6-dichloro-3-(1H-imidazol-2-yl)pyridine (crude 0.85 g, yield 36%) M/z214.0, calc. 212.99. 1H NMR (500 MHz, DMSO) δ 12.51 (s, 1H), 8.31 (d,J=8.1, 1H), 7.74-7.63 (m, 1H), 7.26 (s, 2H)

A mixture of 0.856 g (4.00 mmol) of2,6-dichloro-3-(1H-imidazol-2-yl)pyridine, 704 mg (8.00 mmol) ofethylene carbonate and 2930 mg (9.00 mmol) of cesium carbonate washeated in 25.0 ml of N,N-dimethylformamidefor 13 hours at 90° C. Themixture was filtered, the filtrate concentrated in high vacuum, theresidue purified on 10 g of silica column eluting with 80% of ethylacetate in heptane to give9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine. Yield0.359 g (41%). M/z 222.0, calc. 221.04. 1H NMR (500 MHz, CDCl3) δ 8.84(d, J=8.2, 1H), 7.18 (s, 1H), 7.15 (d, J=8.2, 1H), 7.02 (s, 1H),4.63-4.57 (m, 2H), 4.47-4.41 (m, 2H)

A mixture of 0.359 g (1.62 mmol) of9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine and 0.913g (4.06 mmol) of N-iodosuccinimide in 20.0 ml N,N-dimethylformamide washeated at 80° C. for 60 hours. The mixture was concentrated in vacuum,the residue partitioned between ethyl acetate (40 ml) and 0.1 M aqNa2CO3. The organic extracts were washed with 5% aqueous Na2S2O5, water,brine, dried over Na2SO4 and concentrated in vacuum to give9-chloro-2,3-diiodo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine.Yield 0.644 (84%). M/z 473.9, calc. 472.83. 1H NMR (500 MHz, CDCl3) δ8.85 (d, J=8.2, 1H), 7.19 (s, 1H), 7.16 (d, J=8.2, 1H), 7.03 (s, 1H),4.60 (dd, J=9.9, 5.8, 2H), 4.47-4.42 (m, 2H)

2.0 M of Isopropylmagnesium Chloride in tetrahydrofuran (0.782 mL) wasadded dropwise to a solution of 0.644 g (1.36 mmol) of9-chloro-2,3-diiodo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepinein 12 ml of tetrahydrofuran at −10° C. The mixture was allowed to warmto 15° C. The mixture then was quenched by addition of 20 ml of sat.aqueous NH4Cl and extracted with ethyl acetate. The organic extractswere washed with water, brine, dried over Na2SO4 and concentrated togive9-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine.Yield 448 mg (98%). M/z 348.2, calc. M 346.93. 1H NMR (400 MHz, CDCl3) δ8.83 (d, J=8.2, 1H), 7.16 (dd, J=14.0, 5.9, 1H), 7.10 (s, 1H), 4.61-4.54(m, 2H), 4.41 (dd, J=5.0, 2.9, 2H)

Following the procedures of Examples herein, including Examples 20-22,9-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine wasconverted to9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine.A mixture of 110 mg (0.33 mmol) of9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine,87 mg (1.3 mmol) of methylammonium chloride and 0.23 ml (1.3 mmol) ofN,N-diisopropylethylamine in 3.0 ml of N-methylpyrrolidinone wasmicrowaved for 90 min at 170° C. NMP was removed under high vacuum, theresidue was basified with 1 M Na2CO3 and partitioned between ethylacetate and water. The organic extracts were washed with 5% aqueouscitric acid, water, brine, dried over MgSO4 and concentrated. Theresidue was purified by RP HPLC (acetonitrile gradient) to give 367.Yield 12 mg. M/z 326.3, calc. 325.17. 1H NMR (400 MHz, DMSO) δ 8.37 (d,J=8.6, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 6.96 (s, 1H), 6.34 (d, J=8.6,1H), 5.88 (dt, J=13.0, 6.5, 1H), 4.46 (d, J=9.2, 4H), 2.78 (d, J=2.9,3H), 1.46 (d, J=6.6, 6H)

Example 368(2S,4R)-4-hydroxy-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide368

Following the procedures of Example 339,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland 4-trans-hydroxy-L-prolinamide were reacted and the crude productrecrystallised from IMS to give 368 as a white solid (86 mg, 53%). LCMS:RT=2.19 min, [M+H]+439. ¹H NMR 400 MHz (DMSO-d6) δ: 9.02 (1 H, s), 7.77(1 H, s), 7.40 (1 H, br), 6.90 (1 H, br), 5.90 (1 H, s), 5.87-5.85 (1 H,m), 5.05 (1 H, d, J=3.93 Hz), 4.52-4.41 (4 H, m), 4.39 (1 H, m), 4.31 (1H, m), 3.66 (1 H, dd, J=10.60, 4.98 Hz), 2.22 (3 H, s), 2.16-2.10 (1 H,m), 2.00-1.99 (1 H, m), 1.43 (6 H, dd, J=6.59, 2.86 Hz)

Example 369(2S)-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide369

Following the procedures of Example 339,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland L-prolinamide, were reacted and the crude product recrystallisedfrom IMS to give 369 as a white solid (130 mg, 67%). LCMS: RT=2.48 min,[M+H]+=423. ¹H NMR 400 MHz (DMSO-d6) δ: 9.06 (1 H, s), 7.80 (1 H, s),7.35 (1 H, br), 6.94 (1 H, br), 5.96 (1 H, s), 5.90-5.88 (1 H, m), 4.50(4 H, d, J=17.28 Hz), 4.32 (1 H, m), 3.61 (1 H, m), 3.45 (1 H, m)), 2.26(2 H, s), 2.24-2.15 (1 H, m), 1.98-1.97 (3 H, m), 1.47 (6 H, dd, J=6.59,3.27 Hz)

Example 3701-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)azetidin-3-ol370

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 3-hydroxyazetidine hydrochloride with added DIPEA(2.2 eq.), were reacted and the crude product subjected to flashchromatography (SiO2, gradient 0 to 8% methanol in DCM) thenrecrystallisation from IMS to give 370 as pale green crystals (16 mg,14%). LCMS: RT=2.26 min, [M+H]+368. ¹H NMR 400 MHz (DMSO-d6) δ: 9.09 (1H, s), 7.90 (1 H, d, J=0.63 Hz), 7.84 (1 H, s), 5.95-5.94 (1 H, m), 5.91(1 H, s), 5.70 (1 H, d, J=6.40 Hz), 4.59 (1 H, s), 4.55-4.47 (4 H, m),4.18 (2 H, t, J=7.66 Hz), 3.70 (2 H, dd, J=8.85, 4.66 Hz), 1.48 (6 H, d,J=6.60 Hz)

Example 371(3R)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidin-3-ol371

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and (R)-prolinol hydrochloride with added DIPEA (2.2eq.), were reacted and the crude product recrystallised from methanol togive 371 as a green solid (46 mg, 34%). LCMS: RT=2.26 min, [M+H]+=382.¹H NMR 400 MHz (DMSO-d6) δ: 9.09 (1 H, s), 7.88 (1 H, d, J=0.63 Hz),7.82 (1 H, s), 5.97-5.96 (1 H, m), 5.94 (1 H, s), 4.97 (1 H, d, J=3.62Hz), 4.49-4.48 (4 H, m), 4.39 (1 H, s), 3.53-3.42 (3 H, m), 2.02-2.00 (1H, m), 1.90-1.87 (1 H, m), 1.48 (6 H, d, J=6.60 Hz)

Example 372(1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperidin-4-yl)methanol372

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 4-piperidine methanol, were reacted and the crudeproduct subjected to flash chromatography (SiO2, gradient 0 to 8%methanol in DCM) then recrystallisation from methanol to give 372 as awhite solid (69 mg, 48%). LCMS: RT=2.57 min, [M+H]+=410. ¹H NMR 400 MHz(DMSO-d6) δ: 9.10 (1 H, s), 7.90 (1 H, s), 7.84 (1 H, s), 6.32 (1 H, s),5.99-5.90 (1 H, m), 4.54-4.44 (5 H, m), 4.34 (2 H, d, J=13.11 Hz), 3.28(2 H, t, J=5.64 Hz), 2.84 (2 H, t, J=12.55 Hz), 1.71 (2 H, d, J=13.74Hz), 1.65 (1 H, m), 1.49 (6 H, d, J=6.60 Hz), 1.13 (2 H, t, J=12.33 Hz)

Example 373(2S,4S)-4-fluoro-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide373

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 4-cis-fluoro-L-prolinamide hydrochloride with addedDIPEA (2.2 eq.), were reacted and the crude product recrystallised fromIMS to give 373 as a white solid (56 mg, 22%). LCMS: RT=2.59 min,[M+H]+=427. ¹H NMR 400 MHz (DMSO-d6) δ: 9.05 (1 H, s), 7.84 (1 H, d,J=0.63 Hz), 7.80 (1 H, s), 7.11 (1 H, s), 6.92 (1 H, s), 5.93-5.91 (2 H,m), 5.42 (1 H, s), 5.29 (1 H, s), 4.46-4.44 (5 H, m), 3.83-3.54 (2 H,m), 2.28 (1 H, dd, J=20.28, 14.80 Hz), 1.43 (6 H, dd, J=6.59, 3.60 Hz)

Example 374 (2S,4R)-4-hydroxy-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide374

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 4-trans-hydroxy-L-prolinamide were reacted and thecrude product subjected to flash chromatography (SiO2, gradient 0 to 10%methanol in DCM) to give 374 as a white solid (56 mg, 27%). LCMS:RT=2.16 min, [M+H]+=425. ¹H NMR 400 MHz (DMSO-d6) δ: 9.05 (1 H, s), 7.88(1 H, s), 7.83 (1 H, s), 7.42 (1 H, br), 6.92 (1 H, br), 5.95 (1 H, m),5.92 (1 H, s), 5.07 (1 H, d, J=3.93 Hz), 4.50-4.49 (4 H, m), 4.40 (1 H,m), 4.32 (1 H, m), 3.67 (1 H, t, J=5.33 Hz), 2.16 (1 H, m), 2.04 (1 H,m), 1.47 (6 H, dd, J=6.59, 3.01 Hz)

Example 375(2S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide375

A degassed mixture of 374 mg, (1.00 mmol) of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194, 342.5 mg, (2.000 mmol) of L-Proline tert-Butyl Ester, 26 mg, (0.050mmol) of Bis(tri-t-butylphosphine)palladium and 192 mg, (2.00 mmol) ofSodium tert-butoxide in Toluene (10.0 mL, 93.9 mmol) was heated at 95°C. for 24 hours. The same quantity of L-Proline tert-Butyl Ester, Sodiumtert-butoxide and the catalyst were added and the mixture was heated for6 hours at 115° C. until no starting bromide remains in the reactionmixture. The mixture was concentrated in vacuum, the residue distributedbetween ethyl acetate and 5% aqueous citric acid. The organic extractswere washed with water, sat. NaHCO3, water, brine, dried over MgSO4 andpurified on a silicagel 12 g column eluting with 4% Methanol in DCM togive (S)-tert-butyl1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylate.Yield 153 mg (55-60% purity, the product is contaminated withdebromination byproduct). M/z 465.2, calc. 464.25

Trifluoroacetic acid (3 ml) was added to a mixture of 153 mg of(S)-tert-butyl1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylateand 0.2 ml of triethylsilane in 5 ml of dichloromethane. The reactionmixture was stirred for 3 hours. The mixture was concentrated, theresidue partitioned between 1 M aq. Na2CO3 and ethyl ether. The aqueouslayer was extracted with ethyl acetate two more times. The organiclayers were discarded, the aqueous solution neutralized to pH 6. Aprecipitate was collected, washed with water, dried in high vacuum for36 hours to give(S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylicacid. Yield 55 mg. M/z 409.3, calc. 408.19

A mixture of 55 mg (0.135 mmol) of(S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylicacid, N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate (57.0 mg, 0.150 mmol), N,N-Diisopropylethylamine(52.2 uL, 0.300 mmol) and Ammonium chloride (8.02 mg, 0.150 mmol) inN,N-Dimethylacetamide (3.0 mL, 32 mmol) was stirred for 1 hour. Themixture was concentrated in vacuum, the residue triturated with water,0.01 N aq HCL, water, dried in vacuum and subjected to RP HPLC and thenchiral purification to give 375. Yield 12 mg. M/z 408.2, calc. 407.21.1H NMR (400 MHz, DMSO) δ 8.19 (d, J=8.9, 1H), 7.87 (s, 1H), 7.77 (s,1H), 7.40 (s, 1H), 7.04 (s, 1H), 6.36 (dd, J=9.0, 2.4, 1H), 6.07 (d,J=2.4, 1H), 5.91 (dq, J=13.3, 6.5, 1H), 4.44 (d, J=6.5, 4H), 4.01-3.93(m, 1H), 3.57 (t, J=7.0, 1H), 3.24 (d, J=9.0, 1H), 2.23 (dd, J=12.1,6.9, 1H), 1.98 (dd, J=14.8, 11.3, 3H), 1.47 (dd, J=6.6, 3.3, 6H)

Example 376(2R)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide376

Following the procedures of Example 316,9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 and 1-(tert-butyldimethylsilyloxy)-1-methoxyethene were reacted togive methyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate.M/z 368.2, calc. 367.16

Methyl2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetateand lithium hydroxide were reacted to give2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)aceticacid. M/z 354.1, calc. 353.15

2-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)aceticacid and ammonia were reacted to give 376. M/z 353.1, calc. 352.16. 1HNMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 7.91 (s, 2H), 7.48 (s, 1H),7.04 (d, J=8.2, 1H), 6.97 (s, 1H), 6.92 (s, 1H), 5.95-5.81 (m, 1H), 4.50(d, J=5.8, 4H), 3.38 (s, 2H), 1.48 (d, J=6.5, 6H)

Example 377(2S)-1-(2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide377

Ethylmagnesium bromide (3.0 M in Et2O, 100 mmol, 33.3 mL) was addeddropwise to a solution of9-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine(10.0 g, 28.8 mmol) in tetrahydrofuran (173 mL) at −20° C. The mixturewas maintained at this temperature 20 min and then allowed to warm toambient temperature for a 1 hr period. At this point, the reaction wasre-cooled to −20° C. and N,N-dimethylformamide (8.9 mL, 115 mmol) wasadded to the mixture. Stirring was continued for 16 h before quenchingwith saturated aqueous ammonium chloride solution (220 mL) and furtherdilution with EtOAc (250 mL). The phases were separated and the aqueouslayer was extracted twice with EtOAc. The combined organic portions werewashed once with brine, dried over MgSO4, filtered and concentrated invacuo. This provided 7.08 g (98% yield) of9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine-2-carbaldehydeas a yellow solid in >95% purity as determined by analytical HPLC. MS(ESI+): m/z 249.8 (M+H+), calc. 249.65

To a 100-mL round-bottomed flask was combined9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine-2-carbaldehyde(1.1 g, 4.4 mmol), 40% aqueous solution of ethanedial (2.1 mL, 18.0mmol), ammonium hydroxide (2.55 mL, 65.5 mmol) and methanol (10.5 mL).The resulting reaction mixture was stirred together at room temperaturefor 6 h. At the end of this period, the mixture was evaporated todryness and the oily residue was purified by flash column chromatography(0-100% EtOAc in dichloromethane, slow gradient) to provide 1.13 g (86%yield) of9-chloro-2-(1H-imidazol-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine.

To a solution of9-chloro-2-(1H-imidazol-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine(0.402 g, 1.4 mmol) in N,N-dimethylformamide (9.6 mL) was added Cs2CO3(0.6 g, 2.0 mmol) followed by isopropyl iodide (0.2 mL, 2 mmol). Thereaction mixture was heated at 50° C. for a 20 h period. The mixture wassubsequently cooled to room temperature and diluted with water andEtOAc. The mixture was extracted twice with EtOAc, dried over MgSO4,filtered and concentrated. The resultant residue was purified by flashcolumn chromatography (0-10% MeOH in dichloromethane). This procured0.22 g (48% yield) of9-chloro-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepinewhich was combined with L-prolinamide (0.152 g, 1.33 mmol) inN,N-dimethylacetamide (6.7 mL) and sealed in a pressure vessel. Themixture was heated at 150° C. was heated for 40 h at which point anadditional amount of L-prolinamide (0.152 g, 1.33 mmol) was added andthe mixture was continued to be heated for 12 h. Only 50% conversion wasobserved at the end of this period and heating was discontinued and thematerial was purified by rp-HPLC eluting with 0.1% NH4OH in acetonitrileto provide 19.8 mg (8% yield) of 377. MS (ESI+) m/z 408.2 (M+H+), calcd.408.5. 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 7.58 (s, 1H), 7.43-7.26(m, 2H), 6.89 (d, J=1.0 Hz, 2H), 5.94 (s, 1H), 5.72 (dt, J=13.6, 6.8 Hz,1H), 4.56-4.38 (m, 4H), 4.29 (d, J=8.0 Hz, 1H), 3.59 (s, 1H), 2.17 (d,J=8.9 Hz, 1H), 1.98 (dd, J=31.1, 24.1 Hz, 4H), 1.44 (d, J=4.2 Hz, 6H).

Example 378(2S)-1-(2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide378

To a solution of8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylicacid amide (2.40 g, 0.00907 mol) in Toluene (40 mL) was added1,1-Dimethoxy-N,N-dimethylmethanamine (4.82 mL, 0.0363 mol). The flaskwas sealed and heated to 95° C. for 8 h. The reaction was deemedcomplete by TLC. The solvent was removed in vacuo to give8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylicacid 1-dimethylamino-methylideneamide which was used crude. MS(ESI+)320.1

8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylicacid 1-dimethylamino-methylideneamide (0.00907 mol) was dissolved inAcetic acid (36 mL). 2,4-Difluorophenylhydrazine hydrochloride (1.965 g,0.01088 mol) was added and the reaction was stirred at 95° C. for 2.5hours. The AcOH was removed in vacuo. The crude was triturated in iPrOHto afford 2.828 g (78% yield over 2 steps) of8-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azuleneas a light brown powder clean by 1H NMR. MS(ESI+) 401.1

A solution of8-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene(0.200 g, 0.499 mmol), L-prolinamide (0.171 g, 0.00150 mol) andTriethylamine (0.417 mL, 0.00299 mol) in N-Methylpyrrolidinone (5 mL)under N2 was heated to 150° C. overnight. The mixture was diluted withdichloromethane. Saturated NH4Cl was added and the mixture was extracted3 times with dichloromethane. The organic phases were combined, driedwith Na2SO4 and concentrated. The crude was purified by reverse-phaseHPLC to obtain 94 mg (39% yield) of 378 as a light pink solid. MS(ESI+)479.2. 1H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.18 (s, 1H), 7.86 (s,1H), 7.69 (td, J=8.7, 6.0 Hz, 1H), 7.62-7.53 (m, 1H), 7.35-7.26 (m, 2H),6.92 (br, 1H), 5.84 (s, 1H), 4.47-4.36 (m, 4H), 4.24 (d, J=7.4 Hz, 1H),3.62-3.53 (m, 1H), 3.42-3.32 (m, 1H), 2.24-2.08 (m, 1H), 2.02-1.83 (m,3H)

Example 379(2R)-2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-1-carboxamide379 and Example 380(2S)-2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-1-carboxamide380

To a solution of N-(tert-Butoxycarbonyl)pyrrolidine (1.02 mL, 0.00584mol) and N,N,N′,N′-Tetramethylethylenediamine (0.881 mL, 0.00584 mol) inanhydrous 2-Methoxy-2-methylpropane (12 mL) at −78° C. was addedsec-Butyllithium (0.00584 mol, 1.4M in cyclohexane, 4.17 mL). Thereaction was stirred for 3 hours at −78° C. A solution of Zincdichloride (0.00350 mol, 0.5 M in THF, 7.0 mL) was added dropwise withrapid stirring and was stirred at −78° C. for 30 minutes. The reactionwas then warmed to room temperature and stirred an additional 30mintues. To a N2-filled flask containing8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(0.900 g, 0.00232 mol), Palladium Acetate (0.0260 g, 0.116 mmol) andTri-t-butylphosphonium tetrafluoroborate (0.0420 g, 0.000145 mol) wasadded the zinc chloride pyrrolidine solution (1.25 equiv., 0.243M, 11.9mL). The reaction was heated to 90° C. overnight. An incompleteconversion to product was observed by LC/MS. The mixture was dilutedwith dichloromethane and filtered through celite. Saturated NH4Cl wasadded and the mixture was extracted 3 times with dichloromethane. Theorganic layers were combined, dried with Na2SO4 and concentrated. Thecrude was redissolved in Methylene chloride (4.5 mL). TrifluoroaceticAcid (5.5 mL) was added and the reaction was stirred at room temperaturefor 30 minutes, then concentrated. The crude was purified byreverse-phase HPLC and the enantiomers were separated by chiral SFC toobtain 10 mg of each enantiomer of2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-2-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneas a white solid. MS(ESI+) 379.2

To a solution of2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-2-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(0.009 g, 0.00002 mol) in Acetic acid (4.06 uL, 0.0713 mmol) and water(0.13 mL) was added a solution of Potassium cyanate (0.00579 g, 0.0713mmol) in water (0.13 mL) dropwise. N,N-Dimethylformamide (0.13 mL,0.0017 mol) was added to solubilize the reagents. The reaction wasstirred at 50° C. overnight, cooled down, filtered, and rinsed with coldwater. The crude was purified by precipitation in MeOH/water to give 10mg of each enantiomer 379 and 380. MS (ESI+) 422.2. 1H NMR (400 MHz,DMSO) δ 8.32 (d, J=8.3 Hz, 1H), 7.85 (s, 1H), 6.95 (dd, J=8.3, 1.6 Hz,1H), 6.79 (d, J=1.3 Hz, 1H), 5.90-5.76 (m, 1H), 5.69 (br, 2H), 4.89 (dd,J=7.9, 1.3 Hz, 1H), 4.53-4.44 (m, 4H), 3.58-3.49 (m, 1H), 3.42-3.34 (m,1H), 2.25 (s, 3H), 2.25-2.17 (m, 1H), 1.92-1.65 (m, 3H), 1.45 (dd,J=6.6, 3.9 Hz, 6H).

Example 381(2S)-4,4-difluoro-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide381

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 4,4-difluoro-L-prolinamide hydrochloride with addedDIPEA (2.2 eq.) were reacted and the crude product subjected to RPHPLC(C18 column, gradient 5 to 95% acetonitrile in water+0.1% HCO2H) thenrecrystallisation from IMS to give 381 as a white solid (24 mg, 11%).LCMS: RT=3.21 min, [M+H]+=445. ¹H NMR 400 MHz (DMSO-d6) δ: 9.11 (1 H,s), 7.90 (1 H, d, J=0.64 Hz), 7.87 (1 H, s), 7.53 (1 H, br), 7.14 (1 H,br), 6.08 (1 H, s), 5.99-5.91 (1 H, m), 4.61 (1 H, dd, J=9.53, 4.24 Hz),4.58-4.49 (4 H, m), 4.00-3.98 (2 H, m), 2.91-2.90 (1 H, m), 2.45 (1 H,dd, J=13.51, 4.18 Hz), 1.49 (6 H, dd, J=6.59, 3.35 Hz)

Example 382(2S,4S)-4-fluoro-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide382

Following the procedures of Example 339,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland 4-cis-fluoro-L-prolinamide hydrochloride with added TEA (2.5 eq.),were reacted and the crude product recrystallised from IMS/DCM to give382 as a white solid (68 mg, 42%). LCMS: RT=2.58 min, [M+H]+441. ¹H NMR400 MHz (DMSO-d6) δ: 9.04 (1 H, s), 7.76 (1 H, s), 7.10 (1 H, s), 6.91(1 H, s), 5.95 (1 H, s), 5.87-5.80 (1 H, m), 5.42 (1 H, s), 5.29 (1 H,s), 4.49-4.36 (5 H, m), 3.74-3.73 (2 H, m), 2.46-2.45 (1 H, m), 2.20 (3H, s), 1.40 (6 H, dd, J=6.59, 3.37 Hz)

Example 383(2S)-4,4-difluoro-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide383

Following the procedures of Example 339,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland 4,4-difluoro-L-prolinamide hydrochloride with added TEA (2.5 eq.)were reacted and the crude product subjected to flash chromatography(SiO2, gradient 0 to 5% methanol in DCM) to give 383 as a white solid(29 mg, 17%). LCMS: RT=3.14 min, [M+H]+=459. ¹H NMR 400 MHz (DMSO-d6) δ:9.09 (1 H, s), 7.85 (1 H, d, J=0.64 Hz), 7.55 (1 H, br), 7.15 (1 H, br),6.05 (1 H, s), 5.93-5.81 (1 H, m), 4.61 (1 H, dd, J=9.53, 4.24 Hz),4.58-4.49 (4 H, m), 4.00-3.98 (2 H, m), 2.91-2.90 (1 H, m), 2.45 (1 H,dd, J=13.51, 4.18 Hz), 2.25 (3 H, s), 1.49 (6 H, dd, J=6.59, 3.35 Hz)

Example 384(2S,4S)-4-hydroxy-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide384

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 4-cis-hydroxy-L-prolinamide were reacted and thecrude product recrystallised from IMS to give 384 as a white solid (75mg, 28%). LCMS: RT=2.32 min, [M+H]+425. ¹H NMR 400 MHz (DMSO-d6) δ: 9.08(1 H, s), 7.90 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.47 (1 H, br), 7.13(1 H, br), 6.00 (1 H, s), 5.95-5.94 (1 H, m), 5.28 (1 H, d, J=6.27 Hz),4.51 (4 H, d, J=11.64 Hz), 4.32 (2 H, m), 3.60 (1 H, m), 3.50 (1 H, m),2.42 (1 H, t, J=4.54 Hz), 1.94 (1 H, d, J=13.24 Hz), 1.49 (6 H, dd,J=6.59, 2.75 Hz)

Example 385(2S,4S)-4-hydroxy-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide385

Following the procedures of Example 339,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland 4-cis-hydroxy-L-prolinamide were reacted and the crude productrecrystallised from IMS to give 385 as a white solid (74 mg, 46%). LCMS:RT=2.34 min, [M+H]+439. ¹H NMR 400 MHz (DMSO-d6) δ: 9.05 (1 H, s), 7.79(1 H, s), 7.45 (1 H, br), 7.11 (1 H, br), 5.98 (1 H, s), 5.90-5.84 (1 H,m), 5.27 (1 H, d, J=6.27 Hz), 4.48 (4 H, m), 4.31-4.28 (2 H, m), 3.59 (1H, dd, J=10.61, 4.77 Hz), 3.48 (1 H, d, J=10.45 Hz), 2.40-2.38 (1 H, m),2.24 (3 H, s), 1.93 (1 H, d, J=13.06 Hz), 1.45 (6 H, dd, J=6.59, 2.55Hz)

Example 3862-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine386

9-Chloro-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine(0.044 g, 0.13 mmol), prepared according to Example 377, was taken up inethanol (5 mL) and 20% palladium hydroxide on carbon (19 mg, 0.03 mmol),and glacial acetic acid (0.2 mL) were added. The mixture was subjectedto evacuation under reduced pressure and recycled with an H2 atmosphere.This process was repeated twice. Finally, the reaction was placed underan H2 atmosphere and allowed to stir at ambient temperature 2 h. At theend of this period the mixture was filtered through a pad of Celite® andconcentrated in vacuo. The residue was purified by rp-HPLC (0.1% NH4OHin acetonitrile) to provide 13 mg (39% yield) of 386. MS (ESI+) m/z296.1 (M+H+), calcd. 295.3. 1H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.33(d, J=5.6 Hz, 1H), 7.74 (s, 1H), 7.33 (d, J=1.1 Hz, 1H), 7.03 (d, J=5.6Hz, 1H), 6.92 (d, J=0.9 Hz, 1H), 5.66 (dq, J=13.3, 6.6 Hz, 1H), 4.57(td, J=7.9, 3.5 Hz, 4H), 1.38 (d, J=6.6 Hz, 6H)

Example 387(5-(9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol387

A suspension of8-Chloro-2-[5-methoxymethyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene(500 mg, 1.20 mmol) in 48% aqueous HBr (2.1 mL) was sealed and heated at100° C. for 3 h while carefully monitoring by LCMS. The mixture wascooled to room temperature and poured over a cold solution of 10% KOH.The solid was collect by filtration (˜90% purity by LCMS and ¹H NMRanalysis). The solid was used in subsequent steps without purification.A small amount was purified by HPLC to give 17 mg of 387. LCMS: 401.0.1H NMR (400 MHz, DMSO) δ 9.27 (s, 1H), 8.11 (s, 1H), 7.24 (s, 1H), 5.81(q, J=8.9 Hz, 2H), 5.34 (t, J=6.0 Hz, 1H), 4.71-4.57 (m, 4H), 4.46 (d,J=6.0 Hz, 2H).

Example 388(2R)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)-2,5-dihydro-1H-pyrrole-2-carboxamide388

A solution of 2.64 g (8.00 mmol) of9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine317 in 250 ml of glacial acetic acid was placed into 350 ml glasspressure vessel. The vessel was closed and the mixture was heated for 64hours at 155° C. The mixture was cooled down to room temperature. Whiteprecipitate appeared. The mixture was concentrated to 50 ml volume invacuum, the solid material was filtered out, washed with acetic acid,ethyl ether and dried on air. Weight 1.68 g. The above product wasstirred with 15 ml of sat NaHCO3 for 1 hour, filtered out, washed with2×10 ml of water, dissolved in THF/water (10:1) mixture andconcentrated. The residue was dried in high vacuum for 18 hours to give2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9(10H)-one.Yield 1.12 g (45%). M/z 313.1, calc. 312.13. 1H NMR (400 MHz, DMSO) δ11.79 (s, 1H), 8.41 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 5.84 (s, 1H),5.78 (dt, J=13.2, 6.6, 1H), 4.57-4.51 (m, 2H), 4.50-4.45 (m, 2H), 1.45(d, J=6.6, 6H)

Sodium hydride (192 mg (4.80 mmol) of 60% suspension of in mineral oil)was added to a suspension of 600 mg (1.92 mmol) of2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9(10H)-onein 5.0 ml of dimethylformamide and the mixture was heated at 45° C. for1 hour. N-Phenylbis(trifluoromethanesulphonimide) (1373 mg, 3.842 mmol)was added and the above reaction mixture was heated at 45° C. for 20hours. The mixture was partitioned between ethyl acetate and 5% citricacid, the organic extracts were washed with water (×2), brine, driedover MgSO4 and concentrated. The residue was purified on a 12 g silicacolumn eluting2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yltrifluoromethanesulfonate with 4% MeOH in DCM. Yield 560 mg (66%). M/z445.2, calc. 444.08

A mixture of 134 mg (0.30 mmol) of2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yltrifluoromethanesulfonate,(R)-2,5-dihydro-1H-pyrrole-2-carboxamide (84.1 mg, 0.750 mmol) andN,N-diisopropylethylamine (61.0 uL, 0.350 mmol) in N,N-Dimethylacetamide(3.0 mL, 32 mmol) was heated for 18 hours at 80° C. The mixture wasconcentrated in high vacuum, the residue triturated with 5% aqueouscitric acid. The precipitate was filtered out, washed with aq. citricacid, water, dried in vacuum and purified by RP HPLC (acetonitrilegradient) to give 388. Yield 28 mg. M/z 407.2, calc. 406.19. 1H NMR (400MHz, DMSO) δ 9.08 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.38 (s, 1H),6.98 (s, 1H), 6.13 (dd, J=6.2, 1.9, 1H), 6.02-5.88 (m, 3H), 4.97 (s,1H), 4.52 (dd, J=9.3, 7.1, 4H), 4.39-4.18 (m, 2H), 1.48 (dd, J=6.6, 2.5,6H)

Example 389(2S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)-2,5-dihydro-1H-pyrrole-2-carboxamide389

Following the procedures in Example 388,2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yltrifluoromethanesulfonate and (S)-2,5-dihydro-1H-pyrrole-2-carboxamidewere reacted to give 389. M/z 407.2, calc. 406.19. 1H NMR (400 MHz,DMSO) δ 9.08 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.38 (s, 1H), 6.98 (s,1H), 6.13 (dd, J=6.2, 1.9, 1H), 6.02-5.88 (m, 3H), 4.97 (s, 1H), 4.52(dd, J=9.3, 7.1, 4H), 4.39-4.18 (m, 2H), 1.48 (dd, J=6.6, 2.5, 6H)

Example 390(5-(9-(pyrrolidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol390

(5-(9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol387 was reacted with pyrrolidine to give 390 (13 mg) as a colorlesssolid. LCMS: 436.1. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 7.93 (s, 1H),5.95 (s, 1H), 5.84 (q, J=8.9 Hz, 2H), 5.32 (t, J=6.1 Hz, 1H), 4.50 (m,4H), 4.45 (d, J=6.0 Hz, 2H), 3.41 (m, 4H), 1.95 (m, 4H)

Example 391(2S)-1-(2-(1-(3,5-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide391

(S)-1-(2-Iodo-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl)-pyrrolidine-2-carboxylicacid amide with acetamidine hydrochloride and3,5-difluorophenylhydrazine hydrochloride were reacted following Example420. The crude product was purified by reverse phase HPLC to give 391(13 mg, 11% yield). LCMS: 493.2. 1H NMR (400 MHz, DMSO) δ 8.58 (s, 1H),7.82 (s, 1H), 7.45 (m, 3H), 7.32 (s, 1H), 6.91 (s, 1H), 5.87 (s, 1H),4.45 (m, 4H), 4.25 (d, J=7.8 Hz, 1H), 3.59 (m, 1H), 3.42-3.31 (m, 1H),2.34 (s, 3H), 2.22-2.09 (m, 1H), 2.00-1.86 (m, 3H).

Example 392(2S)-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-ylamino)propanamide392

A solution containing9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine317 (0.1 g, 0.3 mmol), prepared according to Example 377, andL-alaninamide HCl (0.15 g, 1.21 mmol) in N,N-dimethylacetamide (1mL) washeated at 90° C. for 16 h. The crude reaction mixture was directlypurified by rp-HPLC to provide 8 mg (7% yield) of 392. MS (ESI+) m/z383.1 (M+H+), calcd. 383.2. 1H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 7.88(s, 1H), 7.81 (s, 1H), 7.30 (s, 1H), 6.90 (s, 1H), 6.81 (d, J=7.4 Hz,1H), 6.12 (s, 1H), 5.92 (dt, J=13.1, 6.5 Hz, 1H), 4.47 (q, J=5.8 Hz,4H), 4.37-4.21 (m, 1H), 1.47 (dd, J=6.6 Hz, 6H), 1.25 (d, J=7.0 Hz, 3H)

Example 393(2S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)-3,3-dimethylpyrrolidine-2-carboxamide393

Following the procedures of Example 388,2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yltrifluoromethanesulfonate and (S)-3,3-dimethylpyrrolidine-2-carboxamidewere reacted to give 393. M/z 437.2, calc. 436.23. 1H NMR (400 MHz,DMSO) δ 9.05 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.40 (s, 1H), 6.97 (s,1H), 5.95 (dd, J=14.5, 7.9, 2H), 4.49 (dd, J=14.6, 5.6, 4H), 3.90 (s,1H), 3.63 (t, J=8.5, 1H), 3.43 (d, J=7.8, 1H), 1.96 (dd, J=21.1, 9.3,1H), 1.68 (dd, J=11.9, 5.8, 1H), 1.48 (dd, J=6.6, 3.6, 6H), 1.08 (d,J=6.9, 6H)

Example 394(5-(9-(dimethylamino)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol394

(5-(9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol387 was reacted with dimethylamine-HCl to give 394 (11 mg) as acolorless solid. LCMS: 410.1. 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H),7.94 (s, 1H), 6.13 (s, 1H), 5.84 (q, J=8.9 Hz, 2H), 5.32 (t, J=6.1 Hz,1H), 4.50 (m, 4H), 4.45 (d, J=6.0 Hz, 2H), 3.05 (s, 6H)

Example 395(2S,3S)-3-hydroxy-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide395

Following the procedures of Example 339,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland 3-trans-hydroxy-L-prolinamide were reacted and the crude productrecrystallised from Industrial Methylated Spirits (IMS) to give 395 as awhite solid (63 mg, 39%). LCMS: RT=2.23 min, [M+H]+439. ¹H NMR 400 MHz(DMSO-d6) δ: 9.07 (1 H, s), 7.80 (1 H, s), 7.38 (1 H, br), 7.02 (1 H,br), 5.97 (1 H, s), 5.91-5.90 (1 H, m), 5.27 (1 H, d, J=3.77 Hz), 4.50(5 H, m), 4.35 (1 H, t, J=5.08 Hz), 4.27 (2 H, m), 3.65 (1 H, m), 2.25(3 H, s), 2.07 (1 H, m), 1.89 (1 H, m), 1.46 (6 H, dd, J=6.60, 3.78 Hz)

Example 396(2S,3R)-3-hydroxy-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide396

Following the procedures of Example 339,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland 3-cis-hydroxy-L-prolinamide were reacted and the crude productrecrystallised from IMS then triturated in hot IMS to give 396 as awhite solid (37 mg, 23%). LCMS: RT=2.29 min, [M+H]+439. ¹H NMR 400 MHz(DMSO-d6) δ: 9.04 (1 H, s), 7.78 (1 H, s), 7.17 (1 H, br), 6.91 (1 H,br), 5.91 (1 H, s), 5.88 (1 H, m), 5.22 (1 H, d, J=4.70 Hz), 4.47 (4 H,m), 4.24 (1 H, m), 3.64 (1 H, m), 3.37 (1 H, m), 2.24 (3 H, s), 2.07 (2H, m), 2.02 (1 H, m), 1.44 (6 H, dd, J=6.59, 3.11 Hz)

Example 397(2S,3R)-3-hydroxy-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide397

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 3-cis-hydroxy-L-prolinamide were reacted and thecrude product subjected to RPHPLC (C18 column, gradient 15 to 55%methanol in water+0.1% HCO2H) to give 397 as a white powder (11 mg, 6%).LCMS: RT=2.28 min, [M+H]+425. ¹H NMR 400 MHz (DMSO-d6) δ: 9.08 (1 H, s),7.91 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.20 (1 H, br), 6.94 (1 H, br),6.00-5.98 (1 H, m), 5.94 (1 H, s), 5.25 (1 H, d, J=4.81 Hz), 4.51-4.50(4 H, m), 4.47 (1 H, m), 4.27 (1 H, m), 3.68 (1 H, m), 3.41 (1 H, m),2.09-2.08 (1 H, m), 2.04-2.01 (1 H, m), 1.50 (6 H, dd, J=6.59, 3.26 Hz)

Example 398(2S,3S)-3-hydroxy-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide398

Following the procedures of Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 3-trans-hydroxy-L-prolinamide were reacted and thecrude product subjected to RPHPLC (C18 column, gradient 15 to 55%methanol in water+0.1% HCO2H) to give 398 as a white powder (63 mg,39%). LCMS: RT=2.20 min, [M+H]+425. ¹H NMR 400 MHz (DMSO-d6) δ: 9.09 (1H, s), 7.91 (1 H, d, J=0.63 Hz), 7.86 (1 H, s), 7.40 (1 H, br), 7.04 (1H, br), 5.99 (1 H, m), 5.89 (1 H, s), 5.29 (1 H, d, J=3.76 Hz), 4.53 (4H, m), 4.29 (1 H, m), 4.21 (1 H, br), 3.66 (1 H, d, J=m) 3.50 (1 H, m),2.13-2.02 (1 H, m), 1.91 (1 H, dd, J=12.83, 6.39 Hz), 1.50 (6 H, dd,J=6.59, 3.95 Hz)

Example 399(2S)-1-(2-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide399

Following the procedures of Example 378,8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylicacid 1-dimethylamino-methylideneamide was reacted withtrifluoroethylhydrazine to give8-Chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene(MS(ESI+) 385.1/387.1) which was reacted with L-prolineamide to give399. MS(ESI+) 463.2. 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 7.92 (s,1H), 7.33 (s, 1H), 6.91 (s, 1H), 5.94 (s, 1H), 5.86-5.72 (m, 2H),4.55-4.54 (m, 4H), 4.35-4.26 (m, 1H), 3.65-3.56 (m, 1H), 3.43-3.35 (m,1H), 2.28 (s, 3H), 2.22-2.10 (m, 1H), 2.04-1.90 (m, 3H)

Example 400(2S,4R)-4-fluoro-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide400

Following the procedures of Example 339,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland 4-trans-fluoro-L-prolinamide were reacted and the crude productrecrystallised from IMS to give 400 as a white solid (53 mg, 33%). LCMS:RT=2.77 min, [M+H]+441. ¹H NMR 400 MHz (DMSO-d6) δ: 9.01 (1 H, s), 7.75(1 H, s), 7.51 (1 H, s), 7.00 (1 H, s), 5.96 (1 H, s), 6.00-5.66 (1 H,m), 5.46 (1 H, s), 5.33 (1 H, s), 4.45-4.44 (4 H, m), 4.34 (1 H, t,J=8.00 Hz), 3.86 (1 H, s), 3.71 (1 H, ddd, J=36.66, 12.73, 3.36 Hz),2.53-2.52 (1 H, m), 2.20 (3 H, s), 1.40 (6 H, dd, J=6.59, 2.53 Hz)

Example 401(2S,4R)-4-fluoro-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide401

Following the procedures of Example 339,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland 4-trans-fluoro-L-prolinamide were reacted and the crude productrecrystallised from IMS to give a white solid. The mother liquors wereconcentrated in vacuo and the residue subjected to flash chromatography(SiO2, gradient 0 to 10% methanol in DCM) and pure products combined togive 401 as a white solid (45 mg, 28%). LCMS: RT=2.80 min, [M+H]+=427.¹H NMR 400 MHz (DMSO-d6) δ: 9.02 (1 H, s), 7.84 (1 H, d, J=0.63 Hz),7.80 (1 H, s), 7.51 (1 H, s), 7.00 (1 H, s), 5.97 (1 H, s), 5.90-5.89 (1H, m), 5.46 (1 H, s), 5.33 (1 H, s), 4.50-4.43 (4 H, m), 4.34 (1 H, t,J=8.09 Hz), 3.73-3.72 (1 H, m), 2.53-2.52 (1 H, m), 2.13-2.12 (1 H, m),1.43 (6 H, dd, J=6.59, 2.68 Hz).

Example 402(2S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)-2-methylpyrrolidine-2-carboxamide402

Following the procedures for Examples 339 and 408,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland (S)-2-methyl-pyrollidine-2-carboxylic acid amide were reacted. Thecrude product was passed down a Isolute SCX-2 column, eluting withmethanol then 2M NH3 in methanol. The basic fractions were concentratedin vacuo and the resultant residue subjected to reverse phase HPLC (C18column, gradient 15 to 75% Methanol in water+0.1% HCO2H). Theappropriate fractions were evaporated to dryness, passed down an IsoluteNH2 column, eluting with methanol then further triturated in diethylether to give 402 as a white solid. LCMS: RT=2.79 min, [M+H]+=423. ¹HNMR 400 MHz (CD3OD) δ: 9.14 (1 H, s), 7.93 (1 H, s), 7.69 (1 H, s), 6.05(1 H, s), 5.99 (1 H, m), 4.51-4.50 (4 H, m), 3.70 (1 H, m), 3.57 (1 H,m), 3.50 (1 H, m), 2.36-2.33 (1 H, m), 2.10-2.08 (2 H, m), 1.63 (3 H,s), 1.56 (6 H, dd, J=6.63, 2.34 Hz)

Example 4031-isopropyl-4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidine-3-carboxamide403 Step 1:1-Isopropyl-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2,3,6-tetrahydro-pyridine-3-carboxylicacid amide

To a solution of from4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid amide (0.40 g, 0.87 mmol) in DCM (2 mL) and methanol (2 mL) overmolecular sieves (4A) was added acetone (0.26 mL, 3.48 mmol) and aceticacid (50 μl). The reaction mixture was stirred at RT for 1 h beforesodium triacetoxyborohydride (0.73 g, 3.48 mmol) was added. The reactionmixture was stirred at RT for 48 h. Further quantities of acetone (0.26mL, 3.48 mmol) and sodim triacetoxyborohydride (0.73 g, 3.48 mmol) wereadded and the reaction mixture stirred at RT for 16 h. The reactionmixture was diluted with saturated aqueous sodium bicarbonate solutionand extracted with 10% methanol in DCM (3×30 mL). The combined organicextracts were dried (Na2SO4) and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0 to 10%methanol in DCM) to give1-Isopropyl-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2,3,6-tetrahydro-pyridine-3-carboxylicacid amide (153 mg, 38%). ¹H NMR 300 MHz (CDCl3) δ: 8.48 (1 H, d, J=8.49Hz), 7.87 (1 H, s), 7.84 (1H, br, s), 7.63 (1 H, s), 7.35 (1 H, dd,J=8.52, 1.97 Hz), 7.24 (1H, s), 6.28 (1H, m), 6.00 (1 H, m), 5.20 (1H,br, m), 4.48-4.46 (4 H, m), 3.51 (1 H, m), 3.15 (1H, m), 2.85 (1H, m),2.88 (1H, m), 2.65 (1H, m), 1.59 (6 H, dd, J=6.70, 5.29 Hz), 1.12 (6 H,dd, J=6.53, 2.65 Hz).

Step 2

To a solution of1-isopropyl-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid amide (153 mg, 0.33 mmol) in IMS (denatured ethanol) (10 mL) wasadded platinum (IV) oxide (15 mg, 0.06 mmol). The reaction mixture washeated at 50° C. under an atmosphere of hydrogen. The reaction mixturewas cooled to RT, filtered through Celite® and the filtrate concentratedin vacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 10 to 20% methanol in DCM) to give 403 (80 mg, 52%).LCMS: RT=2.61 min, [M+H]+=464. ¹H NMR 400 MHz (DMSO-d6) δ: 8.38 (1 H, d,J=8.33 Hz), 8.15 (1 H, s), 8.04 (1 H, s), 7.04 (1 H, dd, J=8.35, 1.82Hz), 6.89 (1 H, d, J=1.72 Hz), 5.86 (1 H, m), 4.57-4.48 (4 H, m), 3.57(2H, t, J=12.74 Hz), 3.42 (1 H, m), 3.31 (1 H, m), 3.25 (1 H, m), 3.22(1 H, m), 3.04 (1 H, s), 2.60 (1 H, d, J=13.63 Hz), 1.96 (1 H, s), 1.50(6 H, dd, J=6.59, 3.63 Hz), 1.30 (3 H, d, J=6.70 Hz), 1.22 (3 H, d,J=6.70 Hz)

Example 4042-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-ylamino)acetamide404

Following the procedure for Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and glycinamide hydrochloride salt in NMP were heated at85° C. for 20 h. The reaction mixture was cooled and loaded onto anIsolute SCX-2 cartridge, washed with methanol and eluted with 2M ammoniain methanol and appropriate fractions concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient0 to 10% 2M ammonia in methanol in DCM). The solid was recrystallisedfrom methanol to give 404 as a white solid (19 mg, 8%). LCMS: RT=2.14min, [M+H]+=369. ¹H NMR 400 MHz (DMSO-d6) δ: 9.01 (1 H, s), 7.90 (1 H,d, J=0.63 Hz), 7.82 (1 H, s), 7.32 (1 H, br, s), 7.01 (1 H, br, s), 6.11(1 H, s), 5.97-5.88 (1 H, m), 4.49-4.48 (4 H, m), 3.84 (2 H, d, J=4.26Hz), 1.48 (6 H, d, J=6.60 Hz)

Example 405(2S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)-N-methylpyrrolidine-2-carboxamide405

Following the procedures of Example 388,2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yltrifluoromethanesulfonateand (S)—N-methylpyrrolidine-2-carboxamide were reacted to give 405. M/z423.2, calc. 422.22. 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 7.88 (s,1H), 7.83 (s, 1H), 7.74 (d, J=4.3, 1H), 5.95 (p, J=6.7, 2H), 4.58-4.41(m, 4H), 4.35 (d, J=8.5, 1H), 3.67-3.57 (m, 1H), 3.41-3.33 (m, 1H), 2.57(d, J=4.6, 3H), 2.15 (dd, J=10.8, 7.7, 1H), 1.94 (d, J=6.6, 3H), 1.47(dd, J=6.6, 2.4, 6H)

Example 406(2S,3S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)-3-methylpyrrolidine-2-carboxamide406

Following the procedures of Example 388,2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yltrifluoromethanesulfonateand (2S,3S)-3-methylpyrrolidine-2-carboxamide were reacted to give 406.M/z 432.2, calc., calc. 422.22. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H),7.88 (s, 1H), 7.82 (s, 1H), 7.36 (s, 1H), 6.91 (s, 1H), 6.57 (s, 1H),6.01-5.88 (m, 2H), 4.49 (d, J=8.8, 4H), 3.88 (s, 1H), 3.55 (t, J=6.7,2H), 2.32 (dd, J=10.3, 6.4, 1H), 2.18-2.09 (m, 1H), 1.59 (dd, J=12.0,5.7, 1H), 1.48 (dd, J=6.6, 2.9, 6H), 1.10 (d, J=6.9, 3H)

Example 407(2S,4R)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)-4-methoxypyrrolidine-2-carboxamide407

Following the procedure for Examples 339 and 408,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland (2S,4R)-4-methoxy-pyrrolidine-2-carboxylic acid amide were reacted.The reaction mixture was diluted with water passed down an SCX-2cartridge, washed with DCM, ethyl acetate and methanol and productseluted with 2M ammonia in methanol. Appropriate fractions wereconcentrated in vacuo and the resultant residue was triturated indiethyl ether and methanol, filtered and dried to give 407 as beigesolid (45 mg, 32%). LCMS: RT=2.60 min, [M+H]+=439. ¹H NMR 400 MHz(CDCl3) δ: 9.27 (1 H, s), 7.83 (1 H, s), 7.57 (1 H, s), 6.79 (1 H, br,s), 6.00 (1 H, s), 5.98 (1 H, m), 5.29 (1 H, br, s), 4.65 (1 H, dd,J=8.28, 4.87 Hz), 4.49-4.47 (2 H, m), 4.39-4.34 (2 H, m), 4.23 (1 H, t,J=5.53 Hz), 3.74 (1 H, dd, J=10.34, 5.70 Hz), 3.51-3.46 (1 H, m), 3.36(3 H, s), 2.52-2.51 (1 H, m), 2.24-2.23 (1 H, m), 1.55-1.54 (6 H, m)

Example 408(2S,3S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)-3-methoxypyrrolidine-2-carboxamide408 Step 1: (2S,3S)-2-Carbamoyl-3-methoxy-pyrrolidine-1-carboxylic acidtert-butyl ester

(2S,3S)-3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester (518 mg, 2.0 mmol) was stirred in 7M ammonia in methanol(5 mL) for 4 days. The reaction mixture was concentrated in vacuo andthe residue was subjected to flash chromatography (SiO2, gradient 0 to6% methanol in DCM) to give(25,35)-2-Carbamoyl-3-methoxy-pyrrolidine-1-carboxylic acid tert-butylester (153 mg, 31%). ¹H NMR 400 MHz (DMSO-d6) δ: 7.54 (1 H, br, s), 7.09(1 H, br, s), 4.09-4.00 (1 H, m), 3.78 (1 H, m), 3.47 (1 H, m), 3.26 (3H, s), 1.93 (3 H, m), 1.37 (9 H, s)

Step 2: (2S,3S)-3-Methoxy-pyrrolidine-2-carboxylic acid amidehydrochloride salt

(2S,3S)-2-Carbamoyl-3-methoxy-pyrrolidine-1-carboxylic acid tert-butylester (120 mg, 0.49 mmol) was stirred in hydrochloric acid (5 mL, 3M inmethanol) and methanol for 4 h. The reaction mixture was concentrated invacuo and the residue triturated in diethyl ether and methanol to give(2S,3S)-3-Methoxy-pyrrolidine-2-carboxylic acid amide hydrochloride saltas a white solid (69 mg, 38%). ¹H NMR 400 MHz (DMSO-d6) δ: 8.28 (1 H,br, s), 7.82 (1 H, br, s), 4.23 (1 H, m), 4.11-4.10 (1 H, m), 3.37 (1 H,m), 3.35 (3 H, s), 3.19-3.16 (1 H, m), 2.07 (1 H, m), 1.84-1.83 (1 H, m)

Step 3

Following the procedure for Example 339,2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-oland (2S,3S)-3-methoxy-pyrrolidine-2-carboxylic acid amide with addedtriethylamine were reacted. The crude product was washed with water,filtered then triturated in diethyl ether and methanol to give 408 as awhite solid (40 mg, 27%). LCMS: RT=2.68 min, [M+H]+=439. ¹H NMR 400 MHz(CDCl3) δ: 9.31 (1 H, s), 7.86 (1 H, s), 7.59 (1 H, s), 6.99 (1 H, br,s), 6.08 (1 H, s), 6.03 (1 H, m), 5.37 (1 H, br, s), 4.67 (1 H, s),4.53-4.49 (2 H, m), 4.40-4.39 (2 H, m), 4.29 (1 H, m), 3.62-3.57 (1 H,m), 3.52-3.51 (1 H, m), 3.39 (3 H, s), 2.23 (2 H, m), 1.57 (6 H, dd,J=6.68, 3.32 Hz)

Example 409(2S)-1-(2-(1-cyclohexyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide409

Following the procedures of Example 378,8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylicacid 1-dimethylamino-methylideneamide was reacted withcyclohexylhydrazine hydrochloride to give8-Chloro-2-(2-cyclohexyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene(MS(ESI+) 371.2/373.2) which was reacted with L-prolineamide to give409. MS(ESI+) 449.2.

Example 410(2S)-1-(2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide410

Following the procedures of Example 378,8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylicacid 1-dimethylamino-methylideneamide was reacted with2-chlorophenylhydrazine hydrochloride to give8-chloro-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene(MS(ESI+) 399.1/401.1) which was reacted with L-prolineamide to give410. MS(ESI+) 477.1. 1H NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 8.15 (s,1H), 7.79 (s, 1H), 7.72 (dd, J=8.0, 1.1 Hz, 1H), 7.66-7.52 (m, 3H), 7.29(br, 1H), 6.91 (br, 1H), 5.83 (s, 1H), 4.45-4.38 (m, 4H), 4.23 (d, J=7.7Hz, 1H), 3.61-3.53 (s, 1H), 3.40-3.32 (m, 1H), 2.23-2.06 (m, 1H),2.02-1.84 (m, 3H)

Example 413(5-(9-(dimethylamino)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)methanol413

8-Chloro-2-iodo-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene with2-methoxyacetamidine hydrochloride and isopropylhydrazine hydrochloridewere reacted following Example 420 to give8-Chloro-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azuleneafter collection by filtration (1.42 g, 66% yield)

8-Chloro-2-[5-methoxymethyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulenewas reacted with 48% aqueous HBr to give[5-(8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanolafter purification by FCC (CH₂Cl₂/MeOH), 29% isolated yield.

[5-(8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanolwas reacted with dimethylamine-HCl to give 413 (10 mg) as a colorlesssolid. LCMS: 370.2. 1H NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 7.80 (s, 1H),6.13 (s, 1H), 5.98-5.85 (m, 1H), 5.18 (t, J=6.0 Hz, 1H), 4.56-4.44 (m,4H), 4.41 (d, J=6.0 Hz, 2H), 3.05 (s, 6H), 1.47 (d, J=6.6 Hz, 6H)

Example 4144-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamide414 Step 1: 4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-methyl ester

4-Oxo-piperidien-3-carboxylic acid methyl ester hydrochloride (10 g,51.7 mmol) in water (60 mL) was cooled to 0° C. and sodium carbonate(6.0 g, 56.8 mmol) added.

A solution of di-tert-butyl dicarbonate (11.3 g, 51.7 mmol) in THF (48mL) was added dropwise over 15 min and the reaction left at 0° C. for 1hour. Water was added, the mixture extracted with diethyl ether. Thecombined organic extracts were washed with 10% citric acid thensaturated aqueous sodium hydrogen carbonate and then brine, dried(Na2SO4), filtered and concentrated in vacuo to give4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl esteras a yellow oil (13.42 g, 100%). ¹H NMR 300 MHz (CDCl3) δ: 4.08 (2 H,s), 3.82 (3 H, s), 3.77 (1H, m), 3.59 (2 H, t, J=5.93 Hz), 2.40 (2 H, t,J=5.87 Hz), 1.50 (9 H, s).

Step 2:4-Trifluoromethanesulphonyloxy-5,6-dihydro-2H-pyridine-1,3-dicaroxylicacid 1-tert-butyl ester 3-methyl ester

A suspension of sodium hydride (0.31 g, 7.8 mmol) in THF (10 mL) at 0°C. was treated with 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (1.0 g, 3.9 mmol) in THF (4 mL) and stirred for 0.5h. A solution of N-phenyl-bis(trifluoromethanesulphonamide) (1.53 g, 4.3mmol) in THF (3 mL) was added and the reaction mixture stirred at RT for18 h. Water was added and the THF removed in vacuo. Ethyl acetate and10% aqueous sodium carbonate were added, the organic layer separated andthen washed with 10% aqueous sodium carbonate, dried (Na2SO4), filteredand then concentrated in vacuo. The resultant residue was subjected toflash chromatography (SiO2, gradient 0 to 20% ethyl acetate incyclohexane) to give4-Trifluoromethanesulphonyloxy-5,6-dihydro-2H-pyridine-1,3-dicaroxylicacid 1-tert-butyl ester 3-methyl ester as yellow oil (7.98 g, 91%). ¹HNMR 300 MHz (CDCl3) δ: 4.28 (2 H, s), 3.84 (3 H, s), 3.63 (2 H, t,J=5.74 Hz), 2.52-2.51 (2 H, m), 1.49 (9 H, s).

Step 3:4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(0.20 g, 0.49 mmol),4-trifluoromethanesulphonyloxy-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (0.29 g, 0.75 mmol), potassium acetate(0.12 g, 1.22 mmol), Pd(dppf)2Cl2.DCM (0.04 g, 0.05 mmol), DME:IMS:water7:2:1 (5 mL), were sealed in a microwave vial and heated by microwaveirradiation at 120° C. for 10 min. The reaction mixture was cooled toRT, water and DCM were added, the organic layer separated, washed withwater, dried (Na2SO4), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0 to 5%methanol in DCM) to give4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (239 mg, 91%). ¹H NMR 300 MHz(CDCl3) δ: 8.49 (1 H, d, J=8.30 Hz), 7.87 (1 H, d, J=0.64 Hz), 7.64 (1H, s), 6.92 (1 H, dd, J=8.31, 1.80 Hz), 6.84 (1 H, d, J=1.77 Hz), 6.00(1 H, m), 4.49-4.47 (4 H, m), 4.27 (2 H, s), 3.62 (2 H, t, J=5.69 Hz),3.57 (2 H, s), 2.50 (3 H, s), 1.59 (6 H, d, J=6.63 Hz), 1.51 (9 H, s).

Step 4:4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1.3a-diaza-benzo[e]azulen-8-yl]-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (0.629 g, 1.18 mmol) and lithiumhydroxide monohydrate (4.8 mmol) in THF (4 mL) and water (2 mL) wereheated at 60° C. overnight. The reaction mixture was cooled to RT, THFremoved in vacuo and the residue acidified to pH 3 with 1M HCl. Theresultant solid was filtered off, washed with water and dried. Theresultant solid was subjected to flash chromatography (SiO2, gradient 0to 10% methanol in DCM) to give4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester (0.31 g, 51%). ¹H NMR 300 MHz (CDCl3) δ: 8.27 (1H, d, J=8.34 Hz), 7.93 (1 H, s), 7.17 (1 H, s), 7.07 (1H, dd, J=8.31,1.80 Hz), 6.55 (1 H, s), 6.10 (1 H, m), 4.40 (2 H, m), 4.14 (4 H, m),3.67 (2 H, m), 2.50 (2H, m), 1.63 (6 H, d, J=6.58 Hz), 1.54 (9 H, s).

Step 55-Carbamoyl-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-5,6-dihydro-2H-pyridine-1,3-dicarboxlicacid 1-tert-butyl ester (0.921 g, 1.77 mmol) was stirred in DMF (7 mL).EDCI (0.407 g, 2.12 mmol), HOBt (0.286 g, 2.12 mmol) and DIPEA (1.55 mL,8.85 mmol) were added and the reaction stirred at RT for 5 min. Ammoniumchloride (0.284 g, 5.31 mmol) was added and the reaction mixture stirredat RT for 18 h. Ethyl acetate and water were added, the organic layerseparated and washed with water, dried (MgSO4), filtered andconcentrated in vacuo to give5-Carbamoyl-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacdi tert-butyl ester (0.917 g, 1.76 mmol). LCMS RT=3.13 min, [M+H]+=520

Step 6:4-[2-(2-Isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid amide

5-Carbamoyl-4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester was stirred in TFA (1 mL) and DCM (2 mL) for 2 h.The reaction mixture was concentrated in vacuo and the residuetriturated with diethyl ether to give a solid. The solid was thentreated with tetra allylammonium carbonate (polymer bound) (1.84 g, 4.68mmol) in methanol and DCM for 30 min. The resin was filtered off and thefiltrate concentrated in vacuo to give4-[2-(2-Isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid amide (0.40 g, 82%). ¹H NMR 300 MHz (CDCl3) δ: 8.52-8.46 (1 H, m),7.88 (1 H, s), 7.71-7.69 (1 H, m), 7.08 (1 H, dd, J=8.30, 1.82 Hz), 6.98(1 H, d, J=1.79 Hz), 6.01-6.00 (1 H, m), 4.52-4.47 (4 H, m), 3.75 (2 H,s), 3.15 (2 H, t, J=5.82 Hz), 2.51 (2 H, m), 1.60 (6 H, d, J=6.62 Hz).

Step 7

To a solution of4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid amide (0.15 g, 0.35 mmol) in DCM (16 mL) and methanol (8 mL) wasadded formaldehyde (0.053 mL, 37% aq., 0.7 mmol), sodiumtriacetoxyborohydride (0.11 g, 0.52 mmol) and acetic acid (24 μL, 0.42mmol). The reaction mixture was stirred at RT for 16 h. Sodium hydrogencarbonate (aq.) and 10% Methanol in DCM were added to the mixture andthe organic fraction separated, dried (Na2SO4), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 414 (94mg, 62%). LCMS: RT=2.31 min, [M+H]+=434. ¹H NMR 400 MHz (DMSO-d6) δ:8.32 (1 H, d, J=8.35 Hz), 7.92 (1 H, s), 7.91 (1 H, d, J=0.62 Hz), 7.11(1 H, br, s), 7.08 (1 H, dd, J=8.37, 1.83 Hz), 7.02 (1 H, br, s), 6.98(1 H, d, J=1.79 Hz), 5.94-5.86 (1 H, m), 4.53-4.46 (4 H, m), 3.15 (2 H,s), 2.61 (2 H, s), 2.46 (2 H, s), 2.35 (3 H, s), 1.48 (6 H, d, J=6.60Hz)

Example 4154-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1-methyl-1,2,3,6-tetrahydropyridine-3-carboxamide415

To a solution of4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid amide from Example 414 (0.15 g, 0.35 mmol) in DCM (16 mL) andmethanol (8 mL) was added formaldehyde (0.053 mL, 37% aq., 0.7 mmol),sodium triacetoxyborohydride (0.11 g, 0.52 mmol) and acetic acid (24 μL,0.42 mmol). The reaction mixture was stirred at RT for 16 h. Sodiumhydrogen carbonate (aqueous) and 10% methanol in DCM were added to themixture and the organic fraction separated, dried (Na2SO4), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0 to 10% methanol in DCM) to give thetitle compound. The product was triturated with diethyl ether, filteredand dried to give the title compound (24 mg, 16%). LCMS: RT=2.39 min,[M+H]+=434. ¹H NMR 400 MHz (DMSO-d6) δ: 8.33 (1 H, d, J=8.48 Hz), 7.92(1 H, s), 7.91 (1 H, s), 7.32 (1 H, br, s), 7.27 (1 H, dd, J=8.51, 1.92Hz), 7.11 (1 H, d, J=1.86 Hz), 6.90 (1 H, br, s), 6.35 (1 H, d, J=3.82Hz), 5.90-5.89 (1 H, m), 4.51-4.49 (4 H, m), 3.53 (1 H, s), 3.31 (1 H,m), 2.97 (1 H, m), 2.85 (1 H, m), 2.64 (1 H, m), 2.33 (3 H, s), 1.48 (6H, dd, J=6.60, 3.70 Hz)

Example 4162-(1-isopropyl-1H-1,2,4-triazol-5-yl)-N-methyl-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine416

A solution of trifluoro-methanesulfonic acid2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester (100 mg, 0.23 mmol) in NMP was treated with 2M methylamine in THF(1.8 mL, 0.9 mmol) and heated at 85° C. for 20 h then diluted with waterand stirred for 4 h. The precipitate was collected by filtration anddried in vacuo to give 416 as a white solid (19.5 mg, 28%). LCMS:RT=2.26 min, [M+H]+=326. ¹H NMR 400 MHz (DMSO-d6) δ: 9.02 (1 H, s), 7.88(1 H, s), 7.80 (1 H, s), 6.70 (1 H, br, m), 5.95 (1 H, s), 5.91-5.90 (1H, m), 4.47 (4 H, q, J=6.12 Hz), 2.78 (3 H, d, J=4.86 Hz), 1.47 (6 H, d,J=6.60 Hz)

Example 417(5-(9-(3,3-difluoroazetidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)methanol417

[5-(8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanolwas reacted with 3,3-difluoroazetidine-HCl to give 417 (23 mg) as acolorless solid. LCMS: 418.1. 1H NMR (400 MHz, DMSO) δ 9.14 (s, 1H),7.85 (s, 1H), 6.16 (s, 1H), 5.87 (dt, J=13.2, 6.6 Hz, 1H), 5.18 (t,J=6.0 Hz, 1H), 4.60-4.47 (m, 4H), 4.41 (overlapping m, 6H), 1.47 (d,J=6.6 Hz, 6H)

Example 4202-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-9-(2-(2-methylbenzyl)pyrrolidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine420

A solution of8-Chloro-2-iodo-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (2.00 g,0.58 mmol) and acetamidine hydrochloride (0.653 g, 0.69 mmol) dissolvedin DMF (20 mL) and Et3N (4.0 mL) was treated with4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.166 g,0.029 mmol) and Pd(OAc)2 (0.0646 g, 0.029 mmol) under nitrogenatmosphere. The flask was fitted with a balloon of carbon monoxide andthe reaction mixture was heated at 65° C. 2 h. After cooling to r.t. asolution of trifluoroethyl hydrazine (70% wt in H2O, 1.12 g, 0.69 mmol)in acetic acid (5 mL) was added. After 3 h at 65° C. the mixture wascooled and dilute with water.8-Chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulenewas collected by filtration (washed with water and hexanes, dried undervacuum, 1.74 g, 78% yield). 1H NMR (400 MHz, DMSO) δ 9.26 (s, 1H), 8.10(s, 1H), 7.24 (s, 1H), 5.76 (q, J=8.8 Hz, 2H), 4.71-4.53 (m, 4H), 2.29(s, 3H)

A 10 mL microwave vial was charged with8-Chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene(85 mg, 0.22 mmol) and 2-(2-Methyl-benzyl)-pyrrolidine (231 mg, 6 eq).0.5 mL of NMP and 0.5 mL of triethylamine was added. The vial was sealedand heated at 160° C. for 24 h. After cooling to room temperature, thesolution was purified directly by reverse phase HPLC (0.1% NH4OH/ACN).The isolated solid was further purified by chiral SFC (AD column, 35%MeOH isocratic) to give 27 mg of one enantiomer and 29 mg of 420 (48%total yield). LCMS: 524.2. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 9.08(s, 1H), 7.92 (s, 1H), 7.27-7.06 (m, 4H), 5.99 (s, 1H), 5.80 (q, J=8.9Hz, 2H), 4.50 (m, 4H), 4.38 (br s, 1H), 3.49 (t, J=8.6 Hz, 1H), 3.15 (d,J=10.0 Hz, 1H), 2.60-2.53 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 2.10-1.89(m, 2H), 1.81-1.71 (m, 2H)

Example 4212-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-9-(2-(piperidin-1-ylmethyl)pyrrolidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine421

[5-(8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanolwas reacted with was reacted with 1-Pyrrolidin-2-ylmethyl-piperidine togive 421 after reverse phase HPLC (67 mg). LCMS: 542.2

Example 4222-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N,N-dimethyl-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine422

Following the procedures of Examples 413 and 420,9-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepineand dimethylamine were reacted to give 422. LC/MS (ESI+): m/z 408.1(M+H)

Example 4232-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine423

A microwave vial was charged with a suspension of9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411 (0.239 mg, 0.617 mmol) in 3.0 ml ACN/1.0 mL water. To thissuspension was added potassium acetate (182 mg, 1.85 mmol) and1-methylpyrazole boronic acid pinacol ester (154 mg, 740 mmol). Thereaction suspension was degassed by bubbling nitrogen through thestirred mixture via a syringe. After several minutes the syringe wasremoved and tetrakis(triphenylphosphine)palladium(0) (57 mg, 56 mmol)was added and the reaction vial was quickly sealed. The sealed vial wasflash heated in a microwave at 150° C. for 30 minutes. The cooledreaction was diluted with EtOAc and the organic solution was washed withwater ×1, saline ×1 and dried (Na2SO4) before concentration in vacuo.The crude residue was purified by preparative RP-HPLC to give 132 mg of423 (55% theoretical yield). 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.4 Hz,1H), 8.20 (s, 1H), 7.90 (d, J=23.3 Hz, 2H), 7.36 (dd, J=8.4, 1.6 Hz,1H), 7.25 (d, J=1.6 Hz, 1H), 5.83 (dt, J=13.3, 6.6 Hz, 1H), 4.51 (s,4H), 3.87 (s, 3H), 2.25 (s, 3H), 1.47 (d, J=6.6 Hz, 6H)

Example 4242-(3-amino-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carbonitrile424

Following the procedures of Example 425,2-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-amine(150 mg, 0.350 mmol) was converted to 31 mg of 424 (24% theoreticalyield). 1H NMR (400 MHz, DMSO) δ 8.72 (d, J=2.1 Hz, 1H), 7.94 (s, 1H),7.76 (dd, J=8.5, 2.1 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 5.58 (q, J=8.8 Hz,2H), 5.48 (d, J=12.2 Hz, 2H), 4.60 (d, J=9.0 Hz, 4H)

Example 4252-(3-amino-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carbonitrile425

A microwave vial was charged with a solution of2-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-amine(0.200 mg, 0.466 mmol) in 1.0 ml DMF. To this solution was added zinccyanide (160 mg, 1.4 mmol). The reaction mixture was degassed bybubbling nitrogen through the stirred mixture via a syringe. Afterseveral minutes the syringe was removed andBis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(66 mg, 0.093 mmol) was added and the reaction vial was quickly sealed.The sealed vial was flash heated in a microwave at 125° C. for 30minutes. The cooled reaction was diluted with EtOAc and the organicsolution was washed with water ×1, saline ×1 and dried (Na2SO4) beforeconcentration in vacuo. The crude residue was purified by preparativeRP-HPLC to give 81 mg of 425 (38% theoretical yield). 1H NMR (400 MHz,DMSO) δ 8.51 (dd, J=11.8, 5.7 Hz, 1H), 8.07 (d, J=75.8 Hz, 1H),7.78-7.40 (m, 2H), 5.58 (q, J=8.9 Hz, 2H), 5.50 (s, 2H)

Example 426(2S)-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yloxy)propanamide426

2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93, (+)-tert-butyl d-lactate, diisopropylazodicarboxylate(DIAD), and triphenylphosphine were reacted in THF. The crude productwas subjected to flash chromatography (SiO2, gradient 0-5% methanol inDCM) to give(S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionicacid tert-butyl ester as a yellow oil contaminated withtriphenylphosphine oxide, no further purification was undertaken (206mg, 49% based on NMR quantification of PPh3O). LCMS: RT=3.74 min,[M+H]+=441

A solution of(S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9triaza-benzo[e]azulen-8-yloxy]-propionic acid tert-butyl ester (206 mg,0.47 mmol) in HCl in dioxane (4N, 5 mL) was heated at 50° C. for 2 h.The reaction mixture was concentrated in vacuo and the residuetriturated with MeCN. The product was collected by filtration and driedin vacuo at 50° C. to yield(S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionicacid as a beige solid (115 mg, 66%). LCMS: RT=2.72 min, [M+H]+=385

To a solution of(S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionicacid (115 mg, 0.28 mmol) in DMF (3 mL) was added HATU (128 mg, 0.34mmol), ammonium chloride (23 mg, 0.42 mmol) and triethylamine (67 μL,0.42 mmol) and the reaction mixture stirred at room temperature (RT) for5 hours. Further quantities of HATU (106 mg, 0.28 mmol), ammoniumchloride (15 mg, 0.28 mmol) and triethylamine (21 μL, 0.28 mmol) wereadded and the reaction stirred at RT for 16 h. The reaction mixture wasconcentrated in vacuo, the residue dissolved in ethyl acetate (10 mL)and the mixture washed with water extracting with ethyl acetate (3×10mL). The combined organic extracts were washed with brine, dried (MgSO4)and concentrated in vacuo. The resultant residue was subjected toreverse phase preparative HPLC (C-18 column, 10-90% MeCN in water, 0.1%formic acid, 25 min gradient) to yield 426 as a white solid (68 mg,58%). LCMS: RT=3.07 min, [M+H]+=384; 1H NMR (400 MHz, d6-DMSO) 9.05 (1H,s), 7.87 (1H, s), 7.86 (1H, s), 7.38 (1H, s), 7.05 (1H, s), 6.41 (1H,s), 5.87 (1H, sept, J=6.6 Hz), 5.17 (1H, q, J=6.9 Hz), 4.59-4.43 (4H,m), 1.47-1.37 (9H, m)

Example 4272-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yloxy)acetamide427

Following the procedures of Example 426,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and methylglycolate were reacted and the crude productwas subjected to flash chromatography (SiO2, gradient 0-5% methanol inDCM) to give[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-aceticacid methyl ester as a yellow (88 mg, 24%). LCMS: RT=3.09 min,[M+H]+=385

[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-aceticacid methyl ester (88 mg, 0.23 mmol) was dissolved in a solution ofammonia in methanol (7N, 5 mL) and the reaction mixture heated at 50° C.for 2 h, during which a white precipitate formed. The reaction mixturewas concentrated in vacuo and the residue subjected to reverse phasepreparative HPLC (C-18, 10-90% MeCN in water, 0.1% formic acid, 25 mingradient) to yield 427 as a white solid (42 mg, 50%). LCMS: RT=2.85 min,[M+H]+=370; 1H NMR (400 MHz, d6-DMSO) 9.07 (1H, s), 7.88 (1H, s), 7.86(1H, s), 7.41 (1H, s), 7.18 (1H, s), 6.45 (1H, s), 5.87 (1H, sept, J=6.7Hz), 4.66 (2H, s), 4.60-4.44 (4H, m), 1.44 (6H, d, J=6.7 Hz).

Example 4282-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)acetamide428

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol490 (80 mg, 0.26 mmol) in DMF (3 mL) was added 2-bromoacetamide (53 mg,0.39 mmol) and cesium carbonate (109 mg, 0.33 mmol). The reactionmixture stirred at RT for 16 h before being diluted with water. Themixture was extracted with ethyl acetate (3×10 mL) and the combinedorganic extracts, washed with brine, dried (MgSO4) and concentrated invacuo. The residue was subjected to flash chromatography (SiO2, gradient0-10% methanol in DCM) to yield 428 as a white solid (61 mg, 64%). LCMS:RT=6.70 min, [M+H]+=369; 1H NMR (400 MHz, d6-DMSO) 8.28 (1H, d, J=9.8Hz), 7.85 (1H, s), 7.82 (1H, s), 7.51 (1H, s), 7.35 (1H, s), 6.76 (1H,dd, J=9.8, 2.7 Hz), 6.54 (1H, d, J=2.7 Hz), 5.85 (1H, sept, J=6.6 Hz),4.49-4.39 (6H, m), 1.43 (6H, d, J=6.6 Hz).

Example 4292-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yloxy)-2-methylpropanamide429

Following the procedures of Example 426,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and ethyl 2-hydroxyisobutyrate were reacted and thecrude product was subjected to flash chromatography (SiO2, gradient 0-5%methanol in DCM) to give2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionicacid ethyl ester as a yellow oil (103 mg, 40%). LCMS: RT=3.52 min,[M+H]+=427

To a solution of2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionicacid ethyl ester (103 mg, 0.24 mmol) in methanol (5 mL) was added water(0.5 mL) and lithium hydroxide monohydrate (19 mg, 0.48 mmol). Thereaction mixture was heated at 50° C. for 16 h then HCl (1N, aq.) addeduntil pH˜4. The reaction mixture was concentrated in vacuo to give2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionicacid as a yellow solid. LCMS: RT=2.88 min, [M+H]+=399

To a solution of2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionicacid (96 mg, 0.24 mmol) in DMF (3 mL) was added HATU (184 mg, 0.48mmol), ammonium chloride (39 mg, 0.72 mmol) and triethyl amine (100 μL,0.72 mmol) and the reaction mixture stirred at RT for 2 h. The reactionmixture was concentrated in vacuo, the residue dissolved in ethylacetate (10 mL) and the mixture washed with water, extracting with ethylacetate (3×10 mL). The combined organic extracts were washed with brine,dried (MgSO4) and concentrated in vacuo. The residue was subjected toreverse phase preparative HPLC (C-18, 10-90% MeCN in water 0.1% formicacid, 25 min gradient) to yield 429 as a white solid (38 mg, 38%). LCMS:RT=7.36 min, [M+H]+=398; 1H NMR (400 MHz, d6-DMSO) 8.99 (1H, s), 8.11(1H, s), 7.87 (1H, s), 7.86 (1H, s), 7.16 (1H, s), 6.89 (1H, s), 6.37(1H, s), 5.89 (1H, sept, J=6.6 Hz), 4.59-4.42 (4H, m), 1.54 (6H, s),1.44 (6H, d, J=6.6 Hz)

Example 430(2S,4R)-4-cyano-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide430

Following the procedure for Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and (2S,4R)-2-carbamoyl-4-cyano-pyrrolidine-1-carboxylicacid tert-butyl ester were reacted. The crude product was subjected toflash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give430 as an off-white solid (41 mg, 72%). LCMS: RT=2.85 min, [M+H]+=435.¹H NMR 400 MHz (DMSO-d6) δ: 9.08 (1 H, s), 7.88 (1 H, d, J=0.63 Hz),7.85 (1 H, s), 7.56 (1 H, br, s), 7.11 (1 H, br, s), 6.04 (1 H, s),5.94-5.93 (1 H, m), 4.51 (4 H, d, J=15.42 Hz), 4.44 (1 H, d, J=5.97 Hz),3.92 (1 H, dd, J=10.05, 7.55 Hz), 3.72 (1 H, t, J=8.49 Hz), 3.61-3.53 (1H, m), 2.55-2.54 (1 H, m), 2.35 (1 H, ddd, J=12.61, 6.87, 3.63 Hz), 1.47(6 H, dd, J=6.59, 3.21 Hz)

Example 4315-(9-cyclopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine431

A microwave vial was charged with a solution of5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine(100 mg, 0.200 mmol) in 0.500 ml THF and 0.300 mL water. To thissolution was added potassium phosphate (164 mg, 0.770 mol) andcyclopropyl boronic acid pinacol ester (308 mg, 1.48 mol). The reactionsuspension was degassed by bubbling nitrogen through the stirred mixturevia a syringe. After several minutes the syringe was removed andBis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(20 mg, 0.026 mmol) was added and the reaction vial was quickly sealed.The sealed vial was flash heated in a microwave at 130° C. for 30minutes. The cooled reaction was diluted with EtOAc and the organicsolution was washed with water ×1, saline ×1 and dried (Na2SO4) beforeconcentration in vacuo. The crude residue was purified by preparativeRP-HPLC to give 16.7 mg of 431 (14% theoretical yield). 1H NMR (400 MHz,DMSO) δ 8.24 (d, J=8.3 Hz, 1H), 7.69 (s, 1H), 6.85 (d, J=8.4 Hz, 1H),6.74 (s, 1H), 5.73 (dt, J=13.3, 6.8 Hz, 1H), 5.15 (s, 2H), 4.46 (d,J=2.3 Hz, 4H), 2.04-1.86 (m, 1H), 1.40 (d, J=6.6 Hz, 6H), 1.11-0.88 (m,2H), 0.72 (q, J=4.9 Hz, 2H)

Example 4353-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-2-methylpropanamide435 Step 1:(E)-3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-acrylicacid methyl ester

8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene194 (300 mg, 0.80 mmol), methyl methacrylate (129 μLt, 1.20 mmol),triethylamine (168 μL, 1.20 mmol), tri-o-tolyl-phosphane (49 mg, 0.16mmol) and palladium (II) acetate (9 mg, 0.04 mmol) were suspended in DMF(5 mL) and the reaction mixture degassed by bubbling argon through thesuspension. The reaction mixture was heated at 130° C. for 16 h, beforecooling to RT and diluting the mixture with ethyl acetate (10 mL). Thereaction mixture was washed with water, extracted with ethyl acetate(2×10 mL) and the combined organic extracts washed with brine, dried(MgSO4) then concentrated in vacuo. The resultant residue was subjectedto flash chromatography (SiO2, eluting with 0-5% methanol in DCM) toyield(E)-3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-acrylicacid methyl ester as a white solid (181 mg, 57%) LCMS: RT=3.63 min,[M+H]+=394.

Step 2:3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-propionicacid methyl ester

To a solution of(E)-3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-acrylicacid methyl ester (181 mg, 0.46 mmol) in IMS (10 mL) was added palladiumon carbon (200 mg, 10%). The reaction was stirred at RT under anatmosphere of hydrogen for 16 h. More palladium on carbon (200 mg, 10%)was added and the reaction stirred at RT under an atmosphere of hydrogenfor a further 16 h. The reaction mixture was filtered and the filtrateconcentrated in vacuo to give3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-propionicacid methyl ester as a yellow oil (150 mg, 82%). LCMS: RT=3.40 min,[M+H]+=396.

Step 3

To a solution of3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-propionicacid methyl ester (150 mg, 0.38 mmol) in methanol (5 mL) and H2O (0.5mL) was added lithium hydroxide monohydrate (30 mg, 0.76 mmol) and thereaction mixture heated at 45° C. for 72 h. The reaction mixture wasconcentrated in vacuo and the residue azeotroped with acetonitrile (3×10mL). The resultant residue was suspended in DMF (3 mL) and HATU (289 mg,0.76 mmol), ammonium chloride (61 mg, 1.14 mmol) and triethylamine (159μL, 1.14 mmol) added. The reaction mixture was stirred at RT for 30 min.The mixture was diluted with water (15 mL) and extracted with ethylacetate (2×10 mL). The combined organic extracts were washed with brine,dried (MgSO4) and concentrated in vacuo. The resultant residue wassubjected to flash chromatography (SiO2, eluting with 0-10% methanol inDCM) to yield 435 as a white solid (61 mg, 42%). LCMS: RT=7.27 min,[M+H]+=381. ¹H NMR 400 MHz δ (DMSO-d6): 8.25 (1H, d, J=8.4 Hz), 7.86(1H, s), 7.85 (1H, s), 7.21 (1H, br s), 6.93 (1H, dd, J=8.4, 1.8 Hz),6.83 (1H, d, J=1.8 Hz), 6.66 (1H, br s), 5.85 (1H, sept, J=6.7 Hz),4.50-4.39 (4H, m), 2.86-2.74 (1H, m), 2.56-2.42 (2H, m), 1.44 (6H, d,J=6.7 Hz), 0.97 (3H, d, J=6.6 Hz)

Example 436(2S)-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)propanamide436

Following the procedures of Example 426,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol490 and (+)-tert-butyl d-lactate were reacted and the crude product wassubjected to flash chromatography (SiO2, gradient 0-7% methanol in DCM)to give(S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionicacid tert-butyl ester as a yellow solid (70 mg, 62%). LCMS: RT=3.76 min,[M+H]+=440.

To a solution of(S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionicacid tert-butyl ester (64 mg, 0.15 mmol) in DCM (10 mL) was added TFA(0.5 mL) and the reaction mixture stirred at RT for 16 h. The reactionmixture was concentrated in vacuo and the crude carboxylic acid 512dissolved in DMF (2 mL). HATU (130 mg, 0.34 mmol), ammonium chloride (27mg, 0.51 mmol) and triethylamine (71 μL, 0.51 mmol) were added and thereaction mixture stirred at RT for 1 hour. The reaction mixture wasconcentrated in vacuo, the residue dissolved in ethyl acetate (10 mL)and the mixture washed with water extracting with ethyl acetate (3×10mL). The combined organic extracts were washed with brine, dried (MgSO4)and concentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2 gradient 0-10% methanol in ethyl acetate) to yield436 as a white solid (50 mg, 90%). LCMS: RT=3.07 min; [M+H]+=383, 1H NMR(400 MHz, d6-DMSO) 8.26 (1H, d, J=8.6 Hz), 7.81 (1H, s), 7.85 (1H, s),7.51 (1H, s), 7.21 (1H, s), 6.72 (1H, dd, J=8.6, 2.6 Hz), 6.49 (1H, d,J=2.6 Hz), 5.85 (1H, sept, J=6.6 Hz), 4.62 (1H, q, J=6.6 Hz), 4.55-4.36(4H, m), 1.47-1.36 (9H, m)

Alternatively, to a solution of (R)-2-hydroxy-propionamide (10 g, 0.11mmol) and triethylamine (17.2 mL, 0.12 mmol) in THF (130 mL) at 0° C.was added dropwise, methanesulfonyl chloride (9.56 mL, 0.12 mmol)causing a thick white precipitate to form. The reaction mixture wasstirred at RT for 2 hours. The reaction mixture was diluted with water(150 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were washed with brine, dried (MgSO4) and concentratedin vacuo. The resultant residue was triturated with TBME to yieldmethanesulfonic acid (R)-1-carbamoyl-ethyl ester as a white solid (13.1g, 70%). 1H NMR (400 MHz, d6-DMSO) 7.56 (1H, br s), 7.41 (1H, br s),4.91 (1H, t, J=6.6 Hz), 3.23 (3H, s), 1.44 (3H, d, J=6.6 Hz)

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol490 (100 mg, 0.32 mmol), methanesulfonic acid (R)-1-carbamoyl-ethylester (64 mg, 0.38 mmol) and potassium carbonate (67 mg, 0.48 mmol) weresuspended in DMF (3 mL) and the reaction mixture stirred at RT for 24 hthen at 50° C. for 16 h. The reaction mixture was diluted with water (15mL) and extracted with ethyl acetate (3×10 mL). The combined organicextracts were washed with brine, dried (MgSO4) and concentrated invacuo. The resultant residue was subjected flash chromatography (SiO2gradient 0-10% methanol in ethyl acetate) to yield 436 as a white solid(59 mg, 48%). LCMS: RT=3.07 min; [M+H]+=383; 1H NMR (400 MHz, d6-DMSO)8.26 (1H, d, J=8.6 Hz), 7.81 (1H, s), 7.85 (1H, s), 7.51 (1H, s), 7.21(1H, s), 6.72 (1H, dd, J=8.6, 2.6 Hz), 6.49 (1H, d, J=2.6 Hz), 5.85 (1H,sept, J=6.6 Hz), 4.62 (1H, q, J=6.6 Hz), 4.55-4.36 (4H, m), 1.47-1.36(9H, m). ee >99% (chiralpak IC, 1 mL/min, 20% ethanol in heptane, 50 minrun)

Example 4382-(1-isopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-9-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine438

2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yltrifluoromethanesulfonate from Example 463, (97 mg, 0.22 mmol) wasdissolved in N-methylpyrrolidinone (1.4 mL) and treated with(1H-pyrazol-5-yl)methanamine hydrochloride (138 mg, 0.88 mmol) andtriethylamine (0.24 mL, 1.8 mmol). The reaction mixture was heated at120° C. overnight. The mixture was diluted with water and 20% MeOH inDCM and the layers separated. The aqueous phase was extracted intoDCM/MeOH (3×), dried over sodium sulfate, filtered, and concentrated invacuo. The crude residue was purified via HPLC to afford 438 as a whitesolid (20 mg, 29%). LC/MS (ESI+): m/z 392 (M+H). 1H NMR (400 MHz, DMSO)δ 12.57 (s, 1H), 9.03 (s, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.54 (s, 1H),7.07 (t, J=5.6 Hz, 1H), 6.14 (d, J=2.0 Hz, 1H), 6.09 (s, 1H), 5.93 (m,1H), 4.46 (m, 6H), 1.47 (d, J=6.6 Hz, 6H)

Example 4402-(1-isopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-9-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine440

Following the procedures for Example 481,9-bromo-2-(1-isopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.640 mmol) was converted to 440. MS: (ESI+)=354.1

Example 4425-(10-cyclopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-amine442

Following the procedures of Example 431,5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-amine(150 mg, 0.350 mmol) was converted to 8.4 mg of 442 (6.4% theoreticalyield). 1H NMR (400 MHz, DMSO) δ 8.72 (d, J=2.1 Hz, 1H), 7.94 (s, 1H),7.76 (dd, J=8.5, 2.1 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 5.73 (dt, J=13.3,6.8 Hz, 1H), 5.15 (s, 2H), 4.46 (d, J=2.3 Hz, 4H), 2.04-1.86 (m, 1H),1.40 (d, J=6.6 Hz, 6H), 1.11-0.88 (m, 2H), 0.72 (q, J=4.9 Hz, 2H)

Example 4432-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carbonitrile443

A microwave vial was charged with a solution of9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411 (0.300 mg, 0.699 mmol) in 2.0 ml DMF. To this solution was addedzinc cyanide (250 mg, 2.1 mmol). The reaction mixture was degassed bybubbling nitrogen through the stirred mixture via a syringe. Afterseveral minutes the syringe was removed andBis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(100 mg, 0.140 mmol) was added and the reaction vial was quickly sealed.The sealed vial was flash heated in a microwave at 125° C. for 30minutes. The cooled reaction was diluted with EtOAc and the organicsolution was washed with water ×1, saline ×1 and dried (Na2SO4) beforeconcentration in vacuo. The crude residue was purified by preparativeRP-HPLC to give 156 mg of 443 (59% theoretical yield) 1H NMR (400 MHz,DMSO) δ 8.55 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.74-7.46 (m, 2H), 5.79(dt, J=13.1, 6.6 Hz, 1H), 4.57 (s, 4H), 2.29 (d, J=28.5 Hz, 3H), 1.46(d, J=6.6 Hz, 6H)

Example 4442-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylamino)acetamide444 Step 1:[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-aceticacid methyl ester

8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(1.0 g, 2.7 mmol), glycine (2.0 g, 27 mmol), copper (I) iodide (0.2 g,1.08 mmol), trans-4-hydroxy-(L)-proline (0.14 g, 1.08 mmol) andpotassium phosphate (1.14 g, 5.4 mmol) in DMSO (10 mL) were heated undernitrogen at 80° C. for 18 h. The reaction mixture was cooled to RT,concentrated in vacuo, loaded onto an SCX-2 cartridge, washed withmethanol and eluted with 2M ammonia in methanol. Basic fractions werecombined and concentrated in vacuo and the resultant residue wassubjected to flash chromatography (SiO2, gradient 0 to 10% methanol inDCM) to give[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-aceticacid methyl ester (0.407 g, 39% total). ¹H NMR 400 MHz (CDCl3) δ: 8.32(1 H, d, J=8.78 Hz), 7.55 (1 H, s), 7.26 (1 H, s), 6.46 (1 H, dd,J=8.79, 2.45 Hz), 6.18 (1 H, d, J=2.42 Hz), 6.00 (1 H, m), 4.46-4.45 (2H, m), 4.41-4.35 (2 H, m), 3.94 (2 H, d, J=5.39 Hz), 3.80 (3 H, s), 1.59(6 H, t, J=6.88 Hz).

Step 2:[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-aceticacid lithium salt

To a solution of[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-aceticacid methyl ester (407 mg, 0.43 mmol) in dioxane (1 mL) and water (1 mL)was added lithium hydroxide monohydrate (36 mg, 0.86 mmol) and thereaction mixture stirred at RT for 18 h. Water was added and thereaction mixture extracted with DCM. The aqueous phase was filtered andconcentrated in vacuo to give[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-aceticacid lithium salt (130 mg, 81%). LCMS: RT=2.30 min, [M+H]+=369.

Step 3

A mixture of[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-aceticacid lithium salt (130 mg, 0.35 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (82 mg, 0.42 mmol),1-hydroxybenzotriazole hydrate (55 mg, 0.42 mmol) and DIPEA (0.42 mL,1.4 mmol) in DMF (2 mL) was stirred at RT for 5 min before ammoniumchloride (55 mg, 1.05 mmol) was added and the reaction stirred at RT for18 h. The mixture was concentrated in vacuo and the resultant residuetriturated with water. The solid was filtered off, washed with waterthen dried in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 444 (48mg, 37%). LCMS: RT=2.10 min, [M+H]+=368. ¹H NMR 400 MHz (DMSO-d6) δ:8.12 (1 H, d, J=8.80 Hz), 7.88 (1 H, d, J=0.63 Hz), 7.77 (1 H, s), 7.37(1 H, br, s), 7.11 (1 H, br, s), 6.45 (1 H, dd, J=8.84, 2.36 Hz), 6.32(1 H, br, t), 6.10 (1 H, d, J=2.33 Hz), 5.92 (1 H, m), 4.42 (4 H, m),3.63 (2 H, d, J=5.84 Hz), 1.47 (6 H, d, J=6.60 Hz)

Example 4452-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)ethanesulfonamide445 Step 1:(E)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-ethenesulfonicacid amide

8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene194 (400 mg, 1.07 mmol), ethenesulfonic acid amide (172 mg, 1.60 mmol),triethylamine (223 μL, 1.60 mmol), tri-o-tolyl-phosphane (65 mg, 0.21mmol) and palladium (II) acetate (12 mg, 0.05 mmol) were suspended inDMF (5 mL) and the reaction mixture degassed by bubbling argon throughthe suspension. The reaction mixture was heated at 130° C. for 16 h,before cooling to RT and diluting the mixture with ethyl acetate (10mL). The resultant mixture was washed with water, extracted with ethylacetate (2×10 mL) and the combined organic extracts washed with brine,dried (MgSO4) then concentrated in vacuo. The resultant residue wassubjected to flash chromatography (SiO2, eluting with 0-10% methanol inDCM) to yield the title compound as a white solid (151 mg, 35%) LCMS:RT=2.69 min, [M+H]+=401.

Step 2

To a solution of(E)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-ethenesulfonicacid amide (151 mg, 0.38 mmol) in DCM (5 mL) and IMS (2 mL) was added10% palladium on carbon (150 mg, 10%). The reaction mixture was stirredat RT under an atmosphere of hydrogen for 16 h. The reaction mixture wasfiltered and the filtrate concentrated in vacuo. The resultant residuewas subjected to reverse phase preparative HPLC (C18, eluting with10-90% acetonitrile in H2O, 0.1% formic acid, 25 min gradient) to yield445 as a white solid (74 mg, 49%). LCMS: RT=3.24 min, [M+H]+=403. ¹H NMR400 MHz 6 (DMSO-d6): 8.29 (1H, d, J=8.7 Hz), 7.87 (1H, s), 7.86 (1H, s),7.02 (1H, dd, J=8.5, 1.8 Hz), 6.93 (1H, d, J=1.8 Hz), 6.83 (2H, br s),5.84 (1H, sept, J=6.6 Hz), 4.52-4.41 (4H, m), 3.27-3.20 (2H, m),3.02-2.92 (2H, m), 1.44 (6H, d, J=6.6 Hz)

Example 446(R)-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yloxy)propanamide446

Following the procedures of Example 426,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and ethyl-(L)-lactate were reacted and the crude productwas subjected to flash chromatography (SiO2, gradient 0-5% methanol inDCM) to give(R)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionicacid ethyl ester as a yellow oil contaminated with triphenylphosphineoxide, no further purification was undertaken (70 mg, 29% based on NMRquantification of PPh3O). LCMS: RT=3.38 min, [M+H]+=413

To a solution of(R)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionicacid ethyl ester (70 mg, 0.17 mmol) in methanol (5 mL) and water (1 mL)was added lithium hydroxide monohydrate (23 mg, 0.58 mmol) and thereaction mixture stirred at 50° C. for 1 h. The reaction mixture wasconcentrated in vacuo and the resultant residue azeotroped withacetonitrile (3×20 mL). The residue was dissolved in DMF (3 mL), HATU(220 mg, 0.58 mmol), ammonium chloride (46 mg, 0.86 mmol) andtriethylamine (120 μL, 0.86 mmol) added and the reaction mixture stirredat RT for 1.5 h. The reaction mixture was diluted with ethyl acetate,washed with water, extracting with ethyl acetate (3×15 mL). The combinedorganic extracts were washed with brine, dried (MgSO4) and concentratedin vacuo. The residue was subjected to reverse phase preparative HPLC(C-18, 10-90% MeCN in water 0.1% formic acid, 25 min gradient) to yield446 as a white solid (28 mg, 43%). LCMS: RT=3.07 min, [M+H]+=384; 1H NMR(400 MHz, d6-DMSO) 9.05 (1H, s), 7.87 (1H, s), 7.86 (1H, s), 7.38 (1H,br s), 7.05 (1H, br s), 6.41 (1H, s), 5.87 (1H, sept, J=6.6 Hz), 5.17(1H, q, J=6.8 Hz), 4.60-4.43 (4H, m), 1.50-1.34 (9H, m)

Example 4479-(difluoromethyl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine447 Step 1:2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411 (0.5 g, 0.001 mol) and vinyltrifluoroborane/potassium hydride (0.34g, 0.0026 mol) was dissolved in THF (5 mL) and 1 mL H2O (Tremblay-Morinet al (2006) Tetrahedron Letters 47(18):3043-3046). Cesium Carbonate(1.2 g, 0.0039 mol) was added and mixture was degassed with N2 for 10minutes. Tetrakis(triphenylphosphine)palladium(0) (0.074 g, 0.064 mmol)was added. The reaction vessel was sealed and was heated at 110 C in anoil bath overnight. The reaction mixture was cooled to room temperatureand the seal was removed. The crude product was isolated from an aqueousworkup using H2O and brine. The crude product was purified using flashcolumn chromatography (0-10% MeOH in DCM) to give2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.300 g, 89% yield

Step 2:2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carbaldehyde

2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.300 g, 0.000894 mol) was dissolved in THF (20 mL) and H20 (10 mL).Osmium tetroxide (0.550 mL, 0.0716 mmol, 4% wt in water) was addedfollowed by Sodium metaperiodate (0.383 g, 0.00179 mol). The reactionwas stirred overnight at room temperature. The reaction was quenchedusing saturated sodium thiosulfate.2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carbaldehyde(0.302 g, 95.1% yield) was isolated using an aqueous workup and carriedon without further purification

Step 3

2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carbaldehyde(0.289 g, 0.000857 mol) was dissolved in DCM (3 mL) at room temperature.Bis(2-methoxyethyl)aminosulfur trifluoride (0.368 mL, 0.00171 mol) wasadded followed by Ethanol (0.005 mL, 0.0000857 mol). The reaction wasstirred overnight. The reaction was quenched using saturated NaHCO3. Thecrude product was isolated using an aqueous workup and purified viareverse phase chromatography to give 447 (0.0855 g, 27.8% yield)

Example 4522-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yloxy)-3-methylbutanamide452

Following the procedures of Example 426,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 2-hydroxy-3-methyl-butyric acid methyl ester werereacted and subjected to flash chromatography (SiO2, gradient 0-5%methanol in ethyl acetate) to give racemic2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-3-methyl-butyricacid methyl ester as a yellow oil (160 mg, 58%). LCMS: RT=3.60 min,[M+H]+=427

To a solution of2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-3-methyl-butyricacid methyl ester (160 mg, 0.38 mmol) in methanol (5 mL) and water (1mL)was added lithium hydroxide monohydrate (18 mg, 0.45 mmol) and thereaction mixture stirred at 50° C. for 2 h. The reaction mixture wasconcentrated in vacuo and the resultant residue azeotroped withacetonitrile (3×20 mL). The residue was dissolved in DMF (3 mL), HATU(286 mg, 0.75 mmol), ammonium chloride (60 mg, 1.12 mmol) andtriethylamine (157 μL, 1.12 mmol) added and the reaction mixture stirredat RT for 1 h. The reaction mixture was diluted with ethyl acetate,washed with water, extracting with ethyl acetate (3×15 mL). The combinedorganic extracts were washed with brine, dried (MgSO4) and concentratedin vacuo. The residue was subjected to reverse phase preparative HPLC(C-18, 10-90% MeCN in water 0.1% formic acid, 25 min gradient) to yield452 as a white solid (28 mg, 43%). LCMS: RT=3.61 min, [M+H]+=412; 1H NMR(400 MHz, d6-DMSO) 9.04 (1H, s), 7.87 (1H s), 7.86 (1H, s), 7.31 (1H, brs), 7.08 (1H, br s), 6.43 (1H, s), 5.86 (1H, sept, J=6.56 Hz), 4.97 (1H,d, J=4.91 Hz), 4.61-4.43 (4H, m), 2.21-2.08 (1H, m), 1.43 (6H, dd,J=6.6, 3.6 Hz), 0.94 (6H, dd, J=6.6 Hz, 1.5 Hz)

Example 4532-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine453 Step 1:(3,4-Dimethoxy-benzyl)-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-amine

Following the procedure for Example 339,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 and 3,4-methoxybenzylamine in NMP were reacted withheating at 85° C. for 18 hours. Water was added to the reaction mixtureand the precipitate filtered off and dried to give(3,4-Dimethoxy-benzyl)-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-amineas a white solid (378 mg, 51%). ¹H NMR 400 MHz (DMSO-d6) δ: 8.99 (1 H,s), 7.87 (1 H, d, J=0.63 Hz), 7.79 (1 H, s), 7.22 (1 H, br, s), 6.94 (1H, d, J=1.86 Hz), 6.85-6.84 (2 H, m), 6.01 (1 H, s), 5.91 (1 H, m), 4.45(4 H, d, J=5.45 Hz), 4.40 (2 H, d, J=5.98 Hz), 3.72 (3 H, s), 3.70 (3 H,s), 1.45 (6 H, d, J=6.60 Hz).

Step 2

A solution of(3,4-dimethoxy-benzyl)-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-amine(378 mg, 0.82 mmol) and TFA (15 mL) was heated at 40° C. for 5 h. Thereaction mixture was concentrated in vacuo and the residue loaded ontoan SCX-2 cartridge, washing with methanol and eluting with 2M ammonia inmethanol. Basic fractions were combined and then concentrated in vacuo.The resultant residue was subjected to flash chromatography (SiO2,gradient 0 to 10% methanol in DCM) to give 453 as a white solid (140 mg,55% total). LCMS: RT=2.09 min, [M+H]+=312. ¹H NMR 400 MHz (DMSO-d6) δ:8.93 (1 H, s), 7.88 (1 H, s), 7.80 (1 H, s), 6.19 (2 H, br, s), 5.98 (1H, s), 5.90-5.88 (1 H, m), 4.49-4.43 (4 H, m), 1.47 (6 H, d, J=6.61 Hz)

Example 4542-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-10-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine454

A microwave vial was charged with a suspension of10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.160 mg, 0.412 mmol) in 0.861 ml ACN/0.400 mL water. To thissuspension was added potassium acetate (182 mg, 0.00185 mol) and1-methylpyrazole boronic acid pinacol ester (107 mg, 515 mmol). Thereaction suspension was degassed by bubbling nitrogen through thestirred mixture via a syringe. After several minutes the syringe wasremoved and tetrakis(triphenylphosphine)palladium(0) (38 mg, 33 mmol)was added and the reaction vial was quickly sealed. The sealed vial wasflash heated in a microwave at 150° C. for 30 minutes. The cooledreaction was diluted with EtOAc and the organic solution was washed withwater ×1, saline ×1 and dried (Na2SO4) before concentration in vacuo.The crude residue was purified by preparative RP-HPLC to give 132 mg of454 (55% theoretical yield). MS: (ESI+)=390.2

Example 4552-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carbonitrile455

A microwave vial was charged with a solution of10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.200 mg, 0.466 mmol) in 1.4 ml DMF. To this solution was added zinccyanide (160 mg, 1.4 mmol). The reaction mixture was degassed bybubbling nitrogen through the stirred mixture via a syringe. Afterseveral minutes the syringe was removed andBis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(66 mg, 0.093 mmol) was added and the reaction vial was quickly sealed.The sealed vial was flash heated in a microwave at 150° C. for 30minutes. The cooled reaction was diluted with EtOAc and the organicsolution was washed with water ×1, saline ×1 and dried (Na2SO4) beforeconcentration in vacuo. The crude residue was purified by preparativeRP-HPLC to give 455. MS: (ESI+)=335.1

Example 4582-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-ylamino)acetamide458 Step 1: Trifluoro-methanesulphonic acid2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester

Following the procedure described for trifluoro-methanesulfonic acid2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester to give Trifluoro-methanesulphonic acid2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester (174 mg, 79% total). LCMS: RT=3.56 min, [M+H]+=459. ¹H NMR 400 MHz(DMSO-d6) δ: 9.49 (1 H, s), 7.67 (1 H, s), 6.83 (1 H, s), 5.86-5.80 (1H, m), 4.63-4.62 (2 H, m), 4.50-4.46 (2 H, m), 2.40 (3 H, s), 1.55 (6 H,d, J=6.64 Hz).

Step 2

A mixture of trifluoro-methanesulphonic acid2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester (174 mg, 0.38 mmol), 2-amino-acetamide (281 mg, 3.8 mmol) and NMP(2 mL) was heated at 85° C. for 18 hours. The reaction mixture wastreated with water and stirred, the precipitate formed collected byfiltration. The aqueous filtrate was passed down an Isolute SCX-2cartridge washing with methanol and eluting with 2M ammonia in methanol.Appropriate fractions were combined and concentrated in vacuo, theresultant residue subjected to flash chromatography (SiO2, gradient 0 to10% methanol in DCM) to give 458 (24 mg, 17%). LCMS: RT=2.18 min,[M+H]+=383. ¹H NMR 400 MHz (DMSO-d6) δ: 9.00 (1 H, s), 7.78 (1 H, s),7.31 (1 H, br, s), 7.00 (1 H, br, s), 6.94 (1 H, br, t), 6.10 (1 H, s),5.85 (1 H, m), 4.47 (4 H, m), 3.83 (2 H, d, J=5.85 Hz), 2.25 (3 H, s),1.45 (6 H, d, J=6.61 Hz)

Example 4591-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidine-2-carboxamide459 Step 1:1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-2-carboxylicacid

9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 (1.01 g, 2.7 mmol), methyl piccolinate (3.86 g, 27.0 mmol), copper(I) iodide (0.2 g, 1.08 mmol), trans-4-hydroxy(L)proline (0.14 g, 1.08mmol) and potassium phosphate (1.14 g, 5.4 mmol) in DMSO (10 mL) wereheated at 80° C. for 24 hours. The cooled reaction mixture was loadedonto an Isolute SCX-2 cartridge, washed with methanol and eluted with 2Mammonia in methanol. The resultant residue was triturated with diethylether to afford1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-2-carboxylicacid (1.04 g, 87% total). LCMS: RT=2.94 min, [M+H]+=423.

Step 2

A mixture of1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-2-carboxylicacid (1.15 g, 2.73 mmol), EDCI (0.58 g, 3.0 mmol), HOBt (0.41 g, 3.0mmol) and DIPEA (2.34 mL, 13.65 mmol) in DMF was stirred at RT (2 mL)for 5 min before ammonium chloride (0.44 g, 8.18 mmol) was added and thereaction mixture stirred for 18 h. The reaction mixture was concentratedin vacuo and the resultant residue triturated with water before beingsubjected to flash chromatography (SiO2, gradient 0 to 10% methanol inDCM) to give 459 as a white solid (0.08 g, 6%). LCMS: RT=3.48 min,[M+H]+=422. ¹H NMR 400 MHz (DMSO-d6) δ: 8.18 (1 H, d, J=9.06 Hz), 7.89(1 H, d, J=0.63 Hz), 7.80 (1 H, s), 7.31 (1 H, br, s), 7.01 (1 H, br,s), 6.72 (1 H, dd, J=9.16, 2.60 Hz), 6.40 (1 H, d, J=2.54 Hz), 5.92-5.91(1 H, m), 4.44-4.43 (4 H, m), 4.39 (1 H, m), 3.60 (1 H, d, J=12.44 Hz),3.39-3.32 (1 H, m), 2.06 (1 H, d, J=13.57 Hz), 1.75 (2 H, m), 1.58 (3 H,m), 1.48 (6 H, dd, J=6.60, 2.59 Hz)

Example 4632-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine463 Step 1:2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yltrifluoromethanesulfonate

2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-ol(280 mg, 0.87 mmol) was dissolved in N,N-dimethylacetamide (2.3 mL) andtreated with N-(5-chloro-2-pyridyl)triflimide (720 mg, 1.8 mmol) andtriethylamine (0.61 mL, 4.4 mmol). The mixture was stirred overnight at60° C. The reaction mixture was diluted with 1N HCl and ethyl acetate.The layers were separated and the aqueous phase was extracted into ethylacetate (4×). The combined organics were washed with brine (1×), driedover MgSO4, filtered, and absorbed onto celite for purification by flashchromatography [4 g, 0-100% EtOAc in heptane; removes large impurity]followed by a second purification eluting with 0-20% MeOH in DCM toafford2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yltrifluoromethanesulfonate as a dark viscous oil (285 mg, 71%). 1H NMR(400 MHz, DMSO) δ 9.29 (d, J=11.2 Hz, 1H), 7.99 (d, J=6.2 Hz, 1H), 7.36(s, 1H), 5.82 (hept, J=6.7 Hz, 1H), 4.76-4.68 (m, 4H), 2.26 (s, 3H),1.45 (t, J=7.8 Hz, 6H)

Step 2:N-(3,4-dimethoxybenzyl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine

2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yltrifluoromethanesulfonate (790 mg, 1.7 mmol) was dissolved inN-methylpyrrolidinone (11 mL) and treated with veratrylamine (1.0 mL,6.9 mmol) and triethylamine (1.9 mL, 14 mmol). The reaction mixture washeated at 120° C. overnight. The mixture was diluted with water and 20%MeOH in DCM and the layers separated. The aqueous phase was extractedinto DCM/MeOH (3×), dried over sodium sulfate, filtered, and absorbedonto celite for purification by flash chromatography to affordN-(3,4-dimethoxybenzyl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amineas a light yellow solid (190 mg, 23%). 1H NMR (400 MHz, DMSO) δ 8.99 (s,1H), 7.75 (s, 1H), 6.95 (d, J=1.5 Hz, 1H), 6.92 (s, 1H), 6.88 (s, 1H),6.02 (s, 1H), 5.85 (hept, J=6.6 Hz, 1H), 4.65 (s, 1H), 4.50-4.36 (m,6H), 3.73 (s, 6H), 2.24 (s, 3H), 1.44 (d, J=6.6 Hz, 6H)

Step 3

N-(3,4-dimethoxybenzyl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine(190 mg, 0.40 mmol) was dissolved in TFA (3.0 mL) and heated at 65° C.for 30 min. The reaction mixture was cooled to ambient temperature andconcentrated to dryness in vacuo. The crude residue was purified viaHPLC to afford 463 as a white solid (40 mg, 31%). LC/MS (ESI+): m/z 326(M+H). 1H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 7.76 (s, 1H), 6.19 (s,2H), 5.98 (s, 1H), 5.88-5.76 (m, 1H), 4.45 (dd, J=14.4, 5.6 Hz, 4H),2.24 (s, 3H), 1.44 (d, J=6.6 Hz, 6H)

Example 4668-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)-3,8-diazabicyclo[3.2.1]octan-2-one466 Step 1: 3,8-Diaza-bicyclo[3.2.1]octan-2-one

To a solution of 2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (108 mg, 0.48 mmol) in DCM (0.5 mL) at 0° C. was addeddropwise, TFA (0.5 ml) and the reaction mixture stirred for 30 min. Thereaction was warmed to RT and stirred for 1 h before being concentratedin vacuo and triturated with diethyl ether. The resultant residue wassubjected to flash chromatography (Isolute NH2, 50% methanol in DCM) togive 3,8-Diaza-bicyclo[3.2.1]octan-2-one as a white solid (69 mg,quantitative). LCMS): RT=0.32 min, [M+H]+=127. ¹H NMR 400 MHz (DMSO-d6)δ: 7.02 (1 H, br, s), 3.53 (1 H, m), 3.24 (1 H, dd, J=11.00, 4.14 Hz),2.80-2.79 (1 H, m), 2.77 (1 H, m), 1.78 (3 H, m), 1.57-1.56 (1 H, m).

Step 2

To a suspension of2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olfrom Example 93 (137 mg, 0.44 mmol) in NMP (1.2 mL) was added sodiumhydride (60% in mineral oil, 21 mg, 0.53 mmol). The reaction mixture wasstirred at RT for 45 min, then at 45° C. for 45 min then cooled to RT.Phenyl trifluorosulphonimide (189 mg, 0.53 mmol) was added and thereaction stirred at RT for 1 h. 3,8-diaza-bicyclo[3.2.1]octan-2-one (69mg, 0.48 mmol) and triethylamine (77 μL, 0.44 mmol) were added and thereaction mixture heated at 100° C. for 72 h then 120° C. for 7 h. Thereaction mixture was cooled to RT, quenched with water and the resultingsolid filtered and dried in vacuo. The resultant solid was loaded ontoan Isolute SCX-2 cartridge, washed with methanol and eluted with 2Mammonia in methanol. Basic fractions were combined and concentrated invacuo, the resultant residue was subjected to flash chromatography(SiO2, gradient 0 to 10% methanol in DCM) to give 466 (54 mg, 29%).LCMS: RT=2.33 min, [M+H]+=421. ¹H NMR 300 MHz (DMSO-d6) δ: 9.13 (1 H,s), 7.88 (2 H, d, J=8.29 Hz), 7.19 (1 H, br, s), 6.42 (1 H, s), 5.95 (1H, m), 4.53 (4 H, d, J=10.45 Hz), 4.50 (1 H, m), 3.49 (1 H, m), 3.17 (1H, d, J=5.21 Hz), 2.98 (1 H, m), 2.05-2.20 (2 H, m), 1.99 (1 H, m),1.95-1.98 (1 H, m), 1.48 (6 H, dd, J=6.57, 2.41 Hz)

Example 4673-methyl-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)butanamide467

Following the procedures of Example 426,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-oland 2-hydroxy-3-methyl-butyric acid methyl ester were reacted and thecrude product was subjected to flash chromatography (SiO2, gradient0-10% methanol in ethyl acetate) to give racemic3-Methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyricacid methyl ester as a yellow oil contaminated with triphenylphosphineoxide. LCMS: RT=3.70 min, [M+H]+=466

To a solution of3-methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyricacid methyl ester in methanol (5 mL) was added water (0.5 mL) andlithium hydroxide monohydrate (22 mg, 0.57 mmol). The reaction mixturewas heated at 50° C. for 16 h then HCl (1N, aqueous) added until pH˜4.The reaction mixture was concentrated in vacuo. The resultant residuewas dissolved in DMF (3 mL) and HATU (220 mg, 0.57 mmol), ammoniumchloride (46 mg, 0.86 mmol) and triethylamine (120 μL, 0.86 mmol) added.The reaction mixture was stirred at RT for 1 h before being concentratedin vacuo. The residue was dissolved in ethyl acetate (10 mL) and themixture washed with water, extracting with ethyl acetate (3×10 mL). Thecombined organic extracts were washed with brine, dried (MgSO4) andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give467 as a white solid (121 mg, 36%). LCMS: RT=4.05 min, [M+H]+=451; 1HNMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.3 Hz), 8.03 (1H, s), 7.96 (1H,s), 7.47 (1H, br s), 7.25 (1H, br s), 6.74 (1H, dd, J=8.3, 2.5 Hz), 6.51(1H, d, J=2.5 Hz), 5.86 (2H, q, J=8.9 Hz), 4.50-4.40 (4H, m), 4.22 (1H,dd, J=6.2 Hz), 2.08 (1H, oct, J=6.3 Hz), 0.96 (3H, d, J=6.3 Hz), 0.94(3H, d, J=6.4 Hz)

Example 4682-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ol468

8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(2 g, 4.8 mmol), bis(neopentylglycolato)diborane (1.64 g, 7.2 mmol),1,1′-bis(diphenylphosphino)ferrocenepalladium(ii)dichloridedichloromethane (197 mg, 0.24 mmol) and potassium acetate (1.66 g, 16.9mmol) were suspended in dioxane (25 mL) and the mixture degassed bybubbling argon through the mixture. The reaction mixture was heated at90° C. for 2 h before cooling to RT and diluting with DCM (50 mL).Charcoal was added and the mixture stirred at RT for 5 min. The mixturewas filtered and the filtrate washed with water, extracting with DCM(3×20 mL). The combined organic extracts were washed with brine, dried(MgSO4) and concentrated in vacuo. The resultant residue was trituratedwith diethyl ether, filtered and dried in vacuo at 50° C. to give8-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneas a beige solid (1.7 g, 79%). LCMS: RT=2.64 min, [M+H]+=380

To a solution of8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(1.7 g, 3.8 mmol) in IMS was added hydroxylamine hydrochloride (1.58 g,22.8 mmol) and sodium hydroxide (1.22 g, 30.4 mmol). The reactionmixture was stirred at RT for 18 h before being diluted with water (100mL). The reaction mixture was concentrated in vacuo to remove the IMS.The solid which formed was collected by filtration and dried in vacuo toyield 468 as a beige solid (1.1 g, 85%). LCMS: RT=2.81 min, [M+H]+=352

Example 4722-methyl-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)propanamide472

Following the procedures of Example 426,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol,2-hydroxy-3-methyl-butyric acid methyl ester and2-hydroxy-2-methyl-propionic acid ethyl ester were reacted and the crudeproduct was subjected to flash chromatography (SiO2, gradient 0-10%methanol in ethyl acetate) to give2-methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionicacid ethyl ester as a yellow oil contaminated with triphenylphosphineoxide. LCMS: RT=3.68 min, [M+H]+=466

To a solution of2-methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionicacid ethyl ester in methanol (5 mL) was added water (2 mL) and lithiumhydroxide monohydrate (25 mg, 0.62 mmol). The reaction mixture washeated at 50° C. for 30 min then HCl (1N, aqueous) added until pH˜4. Thereaction mixture was concentrated in vacuo. The resultant residue wasdissolved in DMF (3 mL) and HATU (217 mg, 0.56 mmol), ammonium chloride(45 mg, 0.85 mmol) and triethylamine (119 μL, 0.85 mmol) added. Thereaction mixture was stirred at RT for 1 h before being concentrated invacuo. The residue was dissolved in ethyl acetate (10 mL) and themixture washed with water, extracting with ethyl acetate (3×10 mL). Thecombined organic extracts were washed with brine, dried (MgSO4) andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give472 as a white solid (61 mg, 50%). LCMS: RT=3.74 min, [M+H]+=437; 1H NMR(400 MHz, d6-DMSO) 8.21 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.96 (1H, s),7.52 (1H, br s), 7.25 (1H, br s), 6.68 (1H, dd, J=8.9, 2.8 Hz), 6.47(1H, d, J=2.8 Hz), 5.85 (2H, q, J=8.9 Hz), 4.49-4.39 (4H, m), 1.44 (6H,s)

Example 4752-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-(methylsulfonyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine475

A solution of8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene194 (0.050 g, 0.13 mmol) and crushed Potassium phosphate (0.0851 g,0.401 mmol) in N,N-Dimethylformamide (0.5 mL) was thoroughly degassedwith N2. 2-Methylsulfonylphenylboronic acid (0.053 g, 0.27 mmol),Palladium Acetate (0.0015 g, 0.0067 mmol) and S-Phos (0.00686 g, 0.0167mmol) were added and the mixture was heated in the microwave for 30minutes at 180° C. The reaction was diluted with methylene chloride andfiltered through celite. Saturated NH4Cl was added and the mixture wasextracted 3 times with methylene chloride. The organic layers werecombined, dried with Na2SO4 and concentrated. The crude was purified byreverse-phase HPLC to obtain 8.1 mg of 475 as a white solid. MS(ESI+)450.1. 1H NMR (400 MHz, DMSO) δ 8.47 (d, J=8.3 Hz, 1H), 8.11 (dd, J=8.0,1.1 Hz, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.79 (td, J=7.5, 1.3 Hz, 1H),7.70 (td, J=7.8, 1.3 Hz, 1H), 7.45 (dd, J=7.5, 1.1 Hz, 1H), 7.21 (dd,J=8.3, 1.8 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 5.93 (hept, J=6.2 Hz, 1H),4.57 (q, J=5.7 Hz, 4H), 2.93 (s, 3H), 1.50 (d, J=6.6 Hz, 6H)

Example 4762-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)benzamide476

Following the procedures of Example 475,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene194 was reacted with (2-aminocarbonylphenyl)boronic acid to give 476.MS(ESI+) 415.2. 1H NMR (400 MHz, DMSO) δ 8.42 (d, J=8.3 Hz, 1H), 7.95(s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.54-7.39 (m, 4H), 7.34 (s, 1H),7.22 (dd, J=8.3, 1.7 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 5.93 (hept, J=6.2Hz, 1H), 4.55 (q, J=5.7 Hz, 4H), 1.50 (d, J=6.6 Hz, 6H)

Example 4779-(2-ethylphenyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine477

Following the procedures of Example 475,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene194 was reacted with 2-ethylphenylboronic acid to give 477. MS(ESI+)400.2. 1H NMR (400 MHz, DMSO) δ 8.47 (d, J=8.2 Hz, 1H), 7.95 (s, 1H),7.92 (s, 1H), 7.38-7.31 (m, 2H), 7.30-7.23 (m, 1H), 7.20 (d, J=7.3 Hz,1H), 7.12 (dd, J=8.2, 1.7 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 5.93 (hept,J=6.2 Hz, 1H), 4.65-4.41 (m, 4H), 2.61 (q, J=7.6 Hz, 2H), 1.50 (d, J=6.6Hz, 6H), 1.07 (t, J=7.5 Hz, 3H)

Example 478(2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)phenyl)methanol478

Following the procedures of Example 475,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene194 was reacted with 2-(hydroxymethyl)phenylboronic acid to give 478.MS(ESI+) 402.1. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=8.3 Hz, 1H), 7.96(s, 1H), 7.92 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.41 (td, J=7.4, 1.1 Hz,1H), 7.38-7.32 (m, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.20 (dd, J=8.3, 1.6 Hz,1H), 7.09 (d, J=1.5 Hz, 1H), 6.02-5.83 (m, 1H), 5.16 (t, J=5.3 Hz, 1H),4.56 (q, J=6.1 Hz, 4H), 4.45 (d, J=5.3 Hz, 2H), 1.50 (d, J=6.6 Hz, 6H)

Example 4792-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-amine479

Following Example 480,9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411 was converted to 479 as a white solid (15 mg, 7.2%). LC/MS (ESI+):m/z 325 (M+H). 1H NMR (400 MHz, DMSO) δ 8.04 (d, J=8.6 Hz, 1H), 7.71 (s,1H), 6.37 (dd, J=8.7, 2.0 Hz, 1H), 6.17 (d, J=2.0 Hz, 1H), 5.84 (m, 1H),5.51 (s, 2H), 4.39 (m, 4H), 2.23 (s, 3H), 1.43 (d, J=6.6 Hz, 6H)

Example 4802-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-amine480 Step 1: tert-butyl2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylcarbamate

A mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 (250 mg, 0.67 mmol), t-butyl carbamate (390 mg, 3.3 mmol), cesiumcarbonate (440 mg, 1.3 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.10 mmol), andtris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol) wassuspended in 1,4-dioxane (5.2 mL) and heated at 110° C. for 24 hr. Thereaction mixture was cooled to ambient temperature, diluted with DCM,and filtered to remove solids. The crude mixture was absorbed ontocelite for purification by flash chromatography to afford tert-butyl2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylcarbamateas a yellow crystalline solid (170 mg, 61%). 1H NMR (400 MHz, DMSO) δ9.56 (d, J=12.5 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.85 (s,1H), 7.26 (t, J=5.8 Hz, 1H), 7.23-7.14 (m, 1H), 5.89 (hept, J=6.6 Hz,1H), 4.52-4.42 (m, 4H), 1.47 (d, J=6.6 Hz, 6H)

Step 2

tert-butyl2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylcarbamate(170 mg, 0.40 mmol) was dissolved in DCM (3.0 mL) and treated withtrifluoroacetic acid. After 10 min the solvent was removed in vacuo. Thecrude residue was re-dissolved in DCM and the solvent removed once againto provide a golden solid. The crude material was purified via HPLC toafford 480 as an off-white solid (32 mg, 32%). LC/MS (ESI+): m/z 311(M+H). 1H NMR (400 MHz, DMSO) δ 8.05 (d, J=8.6 Hz, 1H), 7.87 (s, 1H),7.75 (s, 1H), 6.38 (d, J=6.4 Hz, 1H), 6.17 (s, 1H), 5.97-5.84 (m, 1H),5.52 (s, 2H), 4.39 (s, 4H), 1.46 (d, J=6.4 Hz, 6H)

Example 4812-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-10-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine481

A microwave vial was charged with a suspension of10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.200 mg, 0.515 mmol) in 2.0 ml THF/0.400 mL water. To this suspensionwas added potassium phosphate (330 mg, 0.0015 mol) and trimethylboroxine(0.14 ml, 1.00 mmol). The reaction suspension was degassed by bubblingnitrogen through the stirred mixture via a syringe. After severalminutes the syringe was removed andBis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(18 mg, 0.02 mmol) was added and the reaction vial was quickly sealed.The sealed vial was flash heated in a microwave at 140° C. for 40minutes. The cooled reaction was diluted with EtOAc and the organicsolution was washed with water ×1, saline ×1 and dried (Na2SO4) beforeconcentration in vacuo. The crude residue was purified by preparativeRP-HPLC to give 481. MS: (ESI+)=324.1

Example 4822-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine482

Following the procedures of Example 481,9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine411 (0.640 mmol) was converted to 482. MS: (ESI+)=324.1

Example 485(2R)-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)propanamide485

Following the procedure of Example 426,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol490 and ethyl-L-lactate were reacted and the crude product was subjectedto flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate)to give(R)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionicacid ethyl ester as a yellow (315 mg, 66%). LCMS: RT=3.44 min,[M+H]+=412

To a solution of(R)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionicacid ethyl ester (315 mg, 0.77 mmol) in methanol (10 mL) was added water(1 mL) and lithium hydroxide monohydrate (46 mg, 1.15 mmol). Thereaction mixture was heated at 50° C. for 16 h then HCl (1N, aq.) addeduntil pH˜4. The reaction mixture was concentrated in vacuo. Theresultant residue was dissolved in DMF (5 mL) and HATU (583 mg, 1.53mmol), ammonium chloride (122 mg, 2.29 mmol) and triethylamine (320 μL,2.29 mmol) added. The reaction mixture was stirred at RT for 1 h beforebeing concentrated in vacuo. The residue was dissolved in ethyl acetate(10 mL) and the mixture washed with water, extracting with ethyl acetate(3×10 mL). The combined organic extracts were washed with brine, dried(MgSO4) and concentrated in vacuo. The resultant residue was subjectedto flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate)and the product crystallised from acetonitrile to give 485 as a whitesolid (75 mg, 26%). LCMS: RT=3.25 min, [M+H]+=383

Example 486(2S)-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)propanamide486

Following the procedure of Example 426,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-oland 2-hydroxy-3-methyl-butyric acid methyl ester and(R)-2-hydroxy-propionic acid tert-butyl ester were reacted and the crudeproduct was subjected to flash chromatography (SiO2, gradient 0-10%methanol in ethyl acetate) to give(S)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionicacid tert-butyl ester as a yellow oil contaminated withtriphenylphosphine oxide. LCMS: RT=3.86 min, [M+H]+=480

A solution of(S)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionicacid tert-butyl ester was dissolved in DCM (3 mL), TFA (0.5 mL) addedand the reaction mixture stirred at RT for 16 h. The reaction mixturewas concentrated in vacuo, and the residue dissolved in DMF (3 mL). HATU(217 mg, 0.56 mmol), ammonium chloride (46 mg, 0.85 mmol) andtriethylamine (119 μL, 0.85 mmol) were added and the reaction mixturestirred at RT for 1 hour. The reaction mixture was concentrated invacuo, the residue dissolved in ethyl acetate (10 mL) and the mixturewashed with water extracting with ethyl acetate (3×10 mL). The combinedorganic extracts were washed with brine, dried (MgSO4) and concentratedin vacuo. The residue was subjected to flash chromatography (SiO2gradient 0-10% methanol in EtOAc) then reverse phase preparative HPLC(C-18, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) then toyield 486 as a white solid (57 mg, 47%). LCMS: RT=3.52 min, [M+H]+=423;1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.95(1H, s), 7.51 (1H, br s), 7.22 (1H, br s), 6.73 (1H, dd, J=8.9, 2.6 Hz),6.50 (1H, d, J=2.6 Hz), 5.86 (1H, q, J=8.9 Hz), 4.64 (1H, q, J=6.6 Hz),4.51-4.38 (4H, m), 1.40 (1H, d, J=6.4 Hz)

Example 487(2R)-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)propanamide487

Following the procedure of Example 426,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol,2-hydroxy-3-methyl-butyric acid methyl ester and (S)-2-hydroxypropionicacid ethyl ester were reacted and the crude product was subjected toflash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) togive(R)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionicacid ethyl ester as a yellow oil contaminated with triphenylphosphineoxide, no further purification was undertaken. LCMS: RT=3.51 min,[M+H]+=452

To a solution(R)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionicacid ethyl ester in methanol (3 mL) was added water (1 mL) and lithiumhydroxide monohydrate (11 mg, 0.42 mmol). The reaction mixture wasstirred at RT for 16 h then HCl (1N, aq.) added until pH˜4. The reactionmixture was concentrated in vacuo. The resultant residue was dissolvedin DMF (3 mL) and HATU (217 mg, 0.56 mmol), ammonium chloride (45 mg,0.85 mmol) and triethylamine (119 μL, 0.85 mmol) added. The reactionmixture was stirred at RT for 1 h before being concentrated in vacuo.The residue was dissolved in ethyl acetate (10 mL) and the mixturewashed with water, extracting with ethyl acetate (3×10 mL). The combinedorganic extracts were washed with brine, dried (MgSO4) and concentratedin vacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 0-10% methanol in ethyl acetate) to give 487 as a whitesolid (49 mg, 40%). LCMS: RT=3.52 min, [M+H]+=423; 1H NMR (400 MHz,d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.95 (1H, s), 7.51 (1H,br s), 7.22 (1H, br s), 6.73 (1H, dd, J=8.9, 2.6 Hz), 6.50 (1H, d, J=2.6Hz), 5.86 (2H, q, J=8.9 Hz), 4.64 (1H, q, J=6.6 Hz), 4.51-4.38 (4H, m),1.40 (3H, d, J=6.4 Hz)

Example 4892-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine489 Step 1:2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol

A solution of8-chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene(4 g, 10.4 mmol) in acetic acid (100 mL) was heated to 150° C. for 65hours. The reaction was cooled, concentrated in vacuo and loaded onto anIsolute SCX-2 cartridge, washing with methanol and eluting with 2Mammonia in methanol. Basic fractions were combined and concentrated invacuo, the resultant residue was subjected to flash chromatography(SiO2, gradient 0 to 10% methanol in DCM) to give2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol.LCMS: RT=2.25 min, [M+H]+=367.33. ¹H NMR 300 MHz (DMSO-d): δ 8.40 (1 H,br, s), 7.94 (1 H, s), 5.85 (1 H, s), 5.77 (1 H, s), 5.73 (2 H, m), 4.56(2 H, m), 4.49 (2 H, m), 2.29 (3 H, s)

Step 2: Trifluoro-methanesulphonic acid2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester

2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olwas converted to Trifluoro-methanesulphonic acid2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester. LCMS: RT=3.65 min, [M+H]+=499.20.

Step 3:(3,4-Dimethoxy-benzyl)-{2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl}amine

trifluoro-methanesulphonic acid2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ylester was converted to(3,4-Dimethoxy-benzyl)-{2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl}amine.LCMS: RT=2.39 min, [M+H]+=516.38. ¹H NMR 300 MHz (DMSO-d6): δ 8.95 (1 H,s), 7.89 (1 H, s), 7.25 (1 H, br, s), 6.95 (1 H, d, J=1.85 Hz),6.86-6.86 (2 H, m), 6.00 (1 H, s), 5.77 (2 H, d, J=8.90 Hz), 4.45 (4 H,d, J=5.44 Hz), 4.39 (2 H, d, J=5.99 Hz), 3.72 (3 H, s), 3.70 (3 H, s),2.26 (3 H, s)

Step 4

(3,4-dimethoxy-benzyl)-{2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl}aminewas converted to 489 with further recrystallisation from methanol. LCMS:RT=2.41 min, [M+H]+=366.22. ¹H NMR 400 MHz (DMSO-d6): δ 8.89 (1 H, s),7.90 (1 H, s), 6.22 (2 H, br, s), 5.98 (1 H, s), 5.82-5.72 (2 H, m),4.46-4.45 (4 H, m), 2.27 (3 H, s)

Example 4902-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ol490

To a solution of8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(473 mg, 1.16 mmol) in IMS (10 mL) was added hydroxylamine hydrochloride(242 mg, 0.39 mmol) and sodium hydroxide (186 mg, 4.65 mmol) and thereaction mixture stirred at RT for 18 h. Further quantities ofhydroxylamine hydrochloride (242 mg, 0.39 mmol) and sodium hydroxide(186 mg, 4.65 mmol) were added and stirring continued for 3 h. Thereaction mixture was diluted with ammonium chloride solution (20 mL,saturated) and extracted with ethyl acetate (3×10 mL). The combinedorganic extracts were dried (MgSO4), concentrated in vauco and theresultant residue subjected to flash chromatography (SiO2, gradient 0-5%methanol in DCM) to yield 490 as a white solid (155 mg, 43%). 1H NMR(400 MHz, CDCl3) δ 8.29 (1H, d, J=8.4 Hz), 7.88 (1H, s), 7.59 (1H, s),6.64 (1H, dd, J=8.4, 2.6 Hz), 6.48 (1H, d, J=2.6 Hz), 5.99 (1H, sept,J=6.7 Hz), 4.44-4.32 (4H, m), 1.58 (6H, d, J=6.7 Hz).

Alternatively,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(9.5 g, 25.4 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (855 mg, 2.0mmol), tris(dibenzylideneacetone)dipalladium (0) (475 mg, 0.5 mmol) andpotassium hydroxide (4.2 g, 76.2 mmol) were suspended in dioxane (29 mL)and water (15 mL). The suspension was degassed with nitrogen and thereaction mixture heated at 90° C. for 1 h. The reaction mixture wasdiluted with water (50 mL) and extracted with ethyl acetate (20 mL). Theaqueous fraction was acidified to pH˜5 by addition of hydrochloric acid(1M) causing a precipitate to form. The suspension was extracted withethyl acetate (3×15 mL). The combined organic extracts were dried(MgSO4), concentrated in vauco. The resultant residue was trituratedwith diethyl ether to yield 490 as an orange solid (3.6 g, 46%). 1H NMR(400 MHz, DMSO-d6) δ 9.90 (1H, br s), 8.22 (1H, d, J=8.9 Hz), 7.88 (1H,s), 7.82 (1H, s), 6.61 (1H, dd, J=8.9, 2.6 Hz), 6.41 (1H, d, J=2.6 Hz),5.90 (1H, sept, J=6.5 Hz), 4.49-4.39 (4H, m), 1.47 (6H, d, J=6.5 Hz)

Also alternatively,

Step 1: 4-Benzyloxy-2-fluoro-benzonitrile

A solution of 2-fluoro-4-hydroxy-benzonitrile (80 g, 0.58 mol),potassium carbonate (162 g, 1.17 mol) and benzyl bromide (76.4 mL, 0.64mol) and potassium iodide (9.6 g, 0.058 mol) in acetone (600 mL) wasstirred at RT and a significant exothermic reaction was observed.Stirring continued for 18 h without cooling. Reaction progress wasmonitored by TLC analysis. The reaction mixture was diluted with H2O(600 mL) and extracted with EtOAc (500 mL×2). The combined organicextracts were washed with saturated aqueous NaCl solution (500 mL),dried over Na2SO4, filtered and concentrated in vacuo. The resultantresidue was triturated in cyclohexane (300 mL) and the crystalline solidwas filtered off and washed to afford 4-Benzyloxy-2-fluoro-benzonitrile(118.2 g, 90%). ¹H NMR (400 MHz, CDCl3): 7.51 (1 H, dd, J=8.70, 7.48Hz), 7.40 (5 H, m), 6.86-6.76 (2 H, m), 5.11 (2 H, s).

Step 2: 4-Benzyloxy-2-fluoro-benzamidine hydrochloride

A solution of 4-benzyloxy-2-fluoro-benzonitrile (84 g, 0.37 mol) in THF(450 mL) under an atmosphere of nitrogen, was cooled to −70° C. Theresultant suspension was treated with a solution of 1M LiHMDS in THF(440 mL, 0.44 mol) over 10 min to reach a maximum temperature of −55° C.The reaction mixture was allowed to warm to RT and stirred for threedays. Reaction progress was monitored by TLC analysis. The reactionmixture was poured onto ice/1M HCl mixture, the pH adjusted to ˜1 byaddition of 6M HCl and washed with EtOAc (500 mL). The organic layer wasextracted with 1M HCl and the combined aqueous extracts washed withEtOAc (500 mL). The acid aqueous extracts were concentrated to lowvolume in vacuo and the resultant solid filtered off, washed with H2Oand dried in vacuo to give 4-Benzyloxy-2-fluoro-benzamidinehydrochloride as a pale cream crystalline solid (74.5 g, 72%). 1H NMR(400 MHz, d6-DMSO): 9.30 (4 H, d, J=10.39 Hz), 7.64 (1 H, t, J=8.59 Hz),7.49-7.35 (5 H, m), 7.19 (1 H, dd, J=12.88, 2.41 Hz), 7.06 (1 H, dd,J=8.77, 2.41 Hz), 5.25 (2 H, s).

Step 3:5-[2-(4-Benzyloxy-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole

A solution of 4-benzyloxy-2-fluoro-benzamidine hydrochloride (74.5 g,0.265 mol) in THF (705 mL) was treated with potassium hydrogen carbonate(106 g, 1.06 mol) and H2O (150 mL). The resultant mixture was heated toreflux to give a white suspension. Whilst maintaining gentle reflux andmechanical stirring (500 rpm) a solution of2-chloro-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (50 g, 0.265mol) was added dropwise over 40 min. The resultant suspension graduallydissolved giving a dark red mixture that was refluxed for 18 h. Themixture was cooled to RT, diluted with saturated aqueous NaCl solution(500 mL) and extracted with EtOAc (500 mL). The organic extract waswashed with saturated aqueous NaCl solution, dried over Na2SO4, filteredand concentrated in vacuo to give a pink solid The solid was trituratedin a mixture of MTBE/pentane (1:1 by volume, 300 mL), collected byfiltration, washed with a MTBE/pentane mixture and dried in vacuo togive5-[2-(4-Benzyloxy-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazoleas a pale pink solid (84 g, 84%). 1H NMR (400 MHz, d6-DMSO): 7.95-7.93(2 H, m), 7.76 (1 H, s), 7.44-7.42 (5 H, m), 7.12 (1 H, dd, J=13.10,2.52 Hz), 7.03 (1 H, dd, J=8.74, 2.47 Hz), 5.90 (1 H, m), 5.21 (2 H, s),1.46 (6 H, d, J=6.60 Hz).

Step 4:2-[2-(4-Benzyloxy-2-fluoro-phenyl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol

A suspension of5-[2-(4-benzyloxy-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole(84 g, 0.22 mol) and [1,3]dioxolan-2-one (48 g, 0.55 mol) in toluene(100 mL) was heated at 130° C. for 7.5 h allowing some solvent toevaporate until reaction was initiated. The cooled reaction mixture wasconcentrated in vacuo and the residue treated with acetonitrile (50 mL),stirred, sonicated and cooled in an ice bath. The resultant solid wascollected by filtration, washed with cold acetonitrile then diethylether and dried in vacuo at 60° C. to give2-[2-(4-Benzyloxy-2-fluoro-phenyl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol(65.2 g, 70%). 1H NMR (400 MHz, CDCl3): 8.04 (1 H, s), 7.80 (1 H, d,J=0.71 Hz), 7.43-7.41 (6 H, m), 6.89 (1 H, dd, J=8.59, 2.50 Hz), 6.79 (1H, dd, J=11.73, 2.47 Hz), 5.93-5.92 (1 H, m), 5.11 (2 H, s), 4.02 (2 H,t, J=4.93 Hz), 3.89 (2 H, t, J=4.96 Hz), 1.49 (6 H, d, J=6.61 Hz). LCMS:RT=3.30 min, [M+H]+=422.

Step 5:8-Benzyloxy-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene

A solution of2-[2-(4-benzyloxy-2-fluoro-phenyl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol(25.0 g, 59.31 mmol) in DMF (890 mL) was treated with sodium hydride(3.51 g, 94.89 mmol) by portionwise addition. The resultant mixture wasstirred for 23 h at RT and quenched with ice and H2O. The precipitatewas collected by filtration, washed with H2O and dried in vacuo at 60°C. to give8-Benzyloxy-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneas an off-white solid (13.9 g, 58%). 1H NMR (400 MHz, CDCl3): 8.43 (1 H,d, J=8.97 Hz), 7.87 (1 H, s), 7.63 (1 H, s), 7.41-7.39 (5 H, m), 6.82 (1H, dd, J=8.98, 2.58 Hz), 6.64 (1 H, d, J=2.55 Hz), 6.00 (1 H, m), 5.10(2 H, s), 4.50-4.48 (2 H, m), 4.42-4.41 (2 H, m), 1.59 (6 H, d, J=6.63Hz). LCMS: RT=3.80 min, [M+H]+=402.

Step 6: A solution of8-benzyloxy-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenein a mixture of EtOAc (350 mL) and IMS (150 mL), under argon atmosphere,was treated with Pd/C. The atmosphere was exchanged with hydrogen andthe resultant reaction mixture was stirred at RT for 20 h. The hydrogenatmosphere was exchanged with argon, the reaction mixture was dilutedwith DCM (˜60 mL), filtered through a pad of Celite and washed with amixture of DCM/IMS (9:1 by volume). The resultant solution wasconcentrated in vacuo to give the title compound as an off-white solid(9.42 g, 51%). More material was recovered by thorough washing of theCelite residue to provide 490 in 83% total yield. 1H NMR (400 MHz,d6-DMSO): 8.22 (1 H, d, J=8.81 Hz), 7.89 (1 H, s), 7.82 (1 H, s), 6.61(1 H, dd, J=8.80, 2.44 Hz), 6.41 (1 H, d, J=2.41 Hz), 5.95-5.86 (1 H,m), 4.45 (4 H, m), 1.47 (6 H, d, J=6.60 Hz). LCMS: RT=2.52 min,[M+H]+=312

Example 4929-(difluoromethoxy)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine492

Following the procedures of the Examples herein,9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 and difluoromethanol were reacted to give 492. LC/MS (ESI+): m/z362.1 (M+H)

Example 4932-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-amine493

To a mixture of2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylicacid (170 mg, 0.45 mmol) and triethylamine (95 uL, 0.68 mmol), in DMF(3.5 mL), was added diphenylphosphonic azide (146 uL, 0.68 mmol) atambient temperature. After 3 h, water (0.45 mL) was added and thereaction mixture was heated at 100° C. After 1 h, the mixture wasdiluted with ethyl acetate and sat. NaHCO3. The aqueous layer wasextracted into ethyl acetate (3×), and the combined organics werefiltered through a plug of celite and concentrated in vacuo. The cruderesidue was purified by preparative HPLC to afford 493 as a white solid(85 mg, 54%). LC/MS (ESI+): m/z 351 (M+H). 1H NMR (400 MHz, DMSO) δ 8.05(s, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 6.38 (dd, J=8.7, 2.2 Hz,1H), 6.18 (d, J=2.2 Hz, 1H), 5.92 (q, J=8.9 Hz, 2H), 5.56 (s, 2H), 4.41(dd, J=12.3, 5.6 Hz, 4H)

Example 494(2S)-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)butanamide494

Following the procedure of Example 426,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol,2-hydroxy-3-methyl-butyric acid methyl ester and (S)-2-hydroxy-butyricacid tert-butyl ester were reacted and the crude product was subjectedto flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate)to give(S)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyricacid tert-butyl ester as a yellow oil contaminated withtriphenylphosphine oxide, no further purification was undertaken. LCMS:RT=4.05 min, [M+H]+=494

To a solution of(S)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyricacid tert-butyl ester in DCM (3 mL) was added TFA (0.5 mL) and thereaction mixture stirred at RT for 16 h. The reaction mixture wasconcentrated in vacuo, and the residue dissolved in DMF (3 mL). HATU(217 mg, 0.56 mmol), ammonium chloride (46 mg, 0.85 mmol) andtriethylamine (119 μL, 0.85 mmol) were added and the reaction mixturestirred at RT for 1 hour. The reaction mixture was concentrated invacuo, the residue dissolved in ethyl acetate (10 mL) and the mixturewashed with water extracting with ethyl acetate (3×10 mL). The combinedorganic extracts were washed with brine, dried (MgSO4) and concentratedin vacuo. The residue was subjected to flash chromatography (SiO2gradient 0-10% methanol in EtOAc) then reverse phase preparative HPLC(C-18 column, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient)to yield 494 as a white solid (49 mg, 39%). LCMS: RT=3.78 min,[M+H]+=437; 1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H,s), 7.96 (1H, s), 7.50 (1H, br s), 7.24 (1H, br s), 6.74 (1H, dd, J=8.9,2.5 Hz), 6.51 (1H, d, J=2.5 Hz), 5.86 (2H, q, J=8.9 Hz), 4.52-4.39 (5H,m), 1.79 (2H, pent, J=7.2 Hz), 0.92 (3H, t, J=7.2 Hz)

Example 495(2R)-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)butanamide495

Following the procedure for Example 426,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol,2-hydroxy-3-methyl-butyric acid methyl ester and (S)-2-hydroxy-butyricacid tert-butyl ester were reacted and the crude product was subjectedto flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate)to give(R)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyricacid tert-butyl ester as a yellow oil contaminated withtriphenylphosphine oxide. LCMS: RT=4.05 min, [M+H]+=494

To a solution of(R)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyricacid tert-butyl ester in DCM (3 mL) was added TFA (0.5 mL) and thereaction mixture stirred at RT for 16 h. The reaction mixture wasconcentrated in vacuo, and the residue dissolved in DMF (3 mL). HATU(217 mg, 0.56 mmol), ammonium chloride (46 mg, 0.85 mmol) andtriethylamine (119 μL, 0.85 mmol) were added and the reaction mixturestirred at RT for 1 hour. The reaction mixture was concentrated invacuo, the residue dissolved in ethyl acetate (10 mL) and the mixturewashed with water extracting with ethyl acetate (3×10 mL). The combinedorganic extracts were washed with brine, dried (MgSO4) and concentratedin vacuo. The residue was subjected to flash chromatography (SiO2gradient 0-10% methanol in EtOAc) then reverse phase preparative HPLC(C-18 column, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient)to yield 495 as a white solid (60 mg, 48%). LCMS: RT=3.78 min,[M+H]+=437; 1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H,s), 7.96 (1H, s), 7.50 (1H, br s), 7.24 (1H, br s), 6.74 (1H, dd, J=8.9,2.5 Hz), 6.51 (1H, d, J=2.5 Hz), 5.86 (2H, q, J=8.9 Hz), 4.52-4.39 (5H,m), 1.79 (2H, pent, J=7.2 Hz), 0.92 (3H, t, J=7.2 Hz)

Example 4962-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-ylamino)acetamide496 Step 1: Trifluoro-methanesulphonic acid2-[2-(2,2,2-trifluoroethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1.3a,9-triaza-benzo[e]azulen-8-ylester

2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-olwas converted to Trifluoro-methanesulphonic acid2-[2-(2,2,2-trifluoroethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1.3a,9-triaza-benzo[e]azulen-8-ylester. LCMS: RT=3.65 min, [M+H]+=485.12.

Step 2

trifluoro-methanesulphonic acid2-[2-(2,2,2-trifluoroethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1.3a,9-triaza-benzo[e]azulen-8-ylester was converted to 496. LCMS: RT=2.33 min, [M+H]+=409.02. ¹H NMR 400MHz (DMSO-d6): δ 8.97 (1 H, s), 8.05 (1 H, s), 7.96 (1 H, s), 7.31 (1 H,br, s), 6.99 (1 H, br, s), 6.95 (1 H, br, t, J=5.89 Hz), 6.10 (1 H, s),5.88 (2 H, q, J=8.86 Hz), 4.48 (4 H, s), 3.84 (2 H, d, J=5.85 Hz)

Example 4999-ethyl-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine499

2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinefrom Example 447 (0.300 g, 0.894 mmol) was dissolved in ethanol (5 mL)and purged with N2.10% Palladium on Carbon (0.1:0.9, Palladium:carbonblack, 0.0952 g) was added. The resulting suspension was placed undervacuum followed by addition of H2 at atm pressure. This process wasrepeated three times to saturate the catalyst. The reaction was stirredfor 18 hours at room temperature. The reaction mixture was filtered andconcentrated to dryness. The crude product was purified using reversephase chromatography to give 499 (0.189 g, 62.9% yield).

Example 501(2S)-3-methyl-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)butanamide501

Following the procedures of Examples 426 and 467,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-oland 2S-hydroxy-3-methyl-butyric acid methyl ester were converted to 501.

Example 502(2R)-3-methyl-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)butanamide502

Following the procedures of Examples 426 and 467,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-oland 2R-hydroxy-3-methyl-butyric acid methyl ester were converted to 502.

Example 513(2S)-3-hydroxy-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)propanamide513

To a solution of (R)-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acidmethyl ester (2.5 g, 15.6 mmol) in methanol (15 mL) was added HCl indioxane (4N, 5 mL, 20 mmol) and the reaction mixture was stirred at RTfor 5 h. The reaction mixture was concentrated in vacuo, the resultantresidue dissolved in THF (20 mL) and imidazole (1.28 g, 18.7 mmol) andtert-butylchlorodimethylsilane (2.47 g, 16.4 mmol) added. The reactionmixture was stirred at RT for 16 h. The reaction mixture was dilutedwith ethyl acetate (10 mL) and the mixture washed with water extractingwith ethyl acetate (3×10 mL). The combined organic extracts were washedwith brine, dried (MgSO4) and concentrated in vacuo. The residue wassubjected to flash chromatography (SiO2 gradient 0-50% EtOAc incyclohexane) to yield(R)-3-(tert-butyl-dimethyl-silanyloxy)-2-hydroxy-propionic acid methylester as a colorless oil (2.29 g, 63%). 1H NMR (400 MHz, CDCl3)4.26-4.20 (1H, m), 3.93 (1H, dd, J=10.1, 3.4 Hz), 3.86 (1H, dd, J=10.1,2.8 Hz), 3.79 (3H, s), 3.01 (1H, d, J=7.8 Hz), 0.88 (9H, s), 0.06 (3H,s), 0.04 (3H, s)

Following the procedures of Example 426,2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-oland (R)-3-(tert-butyl-dimethyl-silanyloxy)-2-hydroxy-propionic acidmethyl ester were reacted and the crude product was subjected to flashchromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give(S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionicacid methyl ester as a yellow oil contaminated with triphenylphosphineoxide. LCMS: RT=4.48 min, [M+H]+=568

(S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionicacid methyl ester was dissolved in ammonia in methanol (7 N, 10 mL) andthe reaction mixture stirred at RT for 48 hr. The reaction mixture wasconcentrated in vacuo and the resultant residue subjected to flashchromatography (SiO2, gradient 0-5% methanol in ethyl acetate) to give(S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionamideas a yellow oil (101 mg, 49% over 2 steps). LCMS: RT=3.78 min,[M+H]+=553

To a solution of(S)-3-(tert-butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionamide(101 mg, 0.18 mmol) in THF (5 mL) was added TBAF (0.22 mL, 1M solutionin THF, 0.22 mmol) and the reaction mixture was stirred at RT for 2 hr.The reaction mixture was diluted with ethyl acetate (10 mL) and water(10 mL) added. A white precipitate formed which was collected byfiltration and dried in vacuo to yield 513 as a white solid (45 mg,56%). LCMS: RT=2.98 min, [M+H]+=439; 1H NMR (400 MHz, d6-DMSO) 8.23 (1H,d, J=8.7 Hz), 8.03 (1H, s), 7.96 (1H, s), 7.50 (1H, br s), 7.30 (1H, brs), 6.77 (1H, dd, J=8.9, 2.7 Hz), 6.54 (1H, d, J=2.6 Hz), 5.86 (2H, q,J=8.9 Hz), 5.09 (1H, t, J=5.8 Hz), 4.54 (1H, t, J=4.9 Hz), 4.50-4.41(4H, m), 3.74-3.67 (2H, m)

Example 524N-((3-aminooxetan-3-yl)methyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-amine524

Following the procedures of Example 551,9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 and 3-(aminomethyl)oxetan-3-amine were reacted to give 524. LC/MS(ESI+): m/z 396.3 (M+H)

Example 525(3-amino-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-3-yl)methanol525

Following the procedures of Example 551,9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 and (3-aminoazetidin-3-yl)methanol were reacted to give 525. LC/MS(ESI+): m/z 396.2 (M+H)

Example 5262-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylamino)acetamide526 Step 1:2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-aceticacid tert-butyl ester

8-bromo-2-[4-(2,2,2-trifluoro-ethyl)-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas converted to2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-aceticacid tert-butyl ester. LCMS: RT=3.62 min, [M+H]+=465. ¹H NMR 300 MHz(CHCl-d): δ 8.24 (1 H, d, J=8.78 Hz), 7.95 (1 H, s), 7.73 (1 H, s), 6.45(1 H, dd, J=8.81, 2.43 Hz), 6.18 (1 H, d, J=2.40 Hz), 5.75 (2 H, d,J=8.45 Hz), 4.49-4.45 (4 H, m), 3.83 (2 H, d, J=5.03 Hz), 1.51 (9 H, s)

Step 2:2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-aceticacid trifluoroacetate salt

2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-aceticacid tert-butyl ester was converted to2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-aceticacid trifluoroacetate salt. LCMS (110165625): RT=2.72 min, [M+H]+=409.

Step 3

Following the amidation procedure in Example 529,2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-aceticacid trifluoroacetate salt was converted to 526. LCMS: RT=3.07 min,[M+H]+=408. ¹H NMR 400 MHz (DMSO-d6): δ 8.05 (1 H, s), 7.91 (1 H, s),7.37 (1 H, br, s), 7.11 (1 H, br, s), 6.46 (1 H, dd, J=8.85, 2.35 Hz),6.35 (1 H, t, J=5.89 Hz), 6.10 (1 H, d, J=2.31 Hz), 5.92 (2 H, q, J=8.88Hz), 4.44 (4 H, q, J=5.80 Hz), 3.64 (2 H, d, J=5.86 Hz)

Example 528cis-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)cyclopropanecarboxamide528

Following the procedures in Example 530,2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-cyclopropanecarboxylicacid was amidated to give the racemic mixture from which 528 wasisolated. LCMS: RT=3.51 min, [M+H]+=419. ¹H NMR 400 MHz (DMSO-d6): δ8.21 (1 H, d, J=8.31 Hz), 8.08 (1 H, s), 8.04 (1 H, s), 7.44 (1 H, br,s), 7.02 (1 H, dd, J=8.37, 1.75 Hz), 6.89 (1 H, d, J=1.67 Hz), 6.65 (1H, br, s), 5.95-5.85 (2 H, m), 4.56-4.41 (4 H, m), 2.38-2.38 (1 H, m),2.03 (1 H, td, J=8.50, 6.06 Hz), 1.48 (1 H, q, J=5.80 Hz), 1.18 (1 H,td, J=8.18, 4.41 Hz)

Example 5292S)-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylamino)propanamide529 Step 1:(S)-2-{2-[2-(2,2,2-Trifluoro-ethyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-propionicacid tert-butyl ester

A vessel was charged with8-bromo-2-[4-(2,2,2-trifluoro-ethyl)-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(200 mg, 0.48 mmol), alanine tert-butyl ester hydrochloride (434 mg, 2.4mmol), cesium carbonate (1.25 g, 3.84 mmol), 1,3-diisopropylimidazoliumchloride (20 mg, 0.1 mmol) and DME (2 mL), evacuated and refilled withargon. Bis(1,5-cyclooctadiene)rhodium tetrafluororoborate complex (20mg, 0.05 mmol) was added and degassing repeated before the reactionmixture was heated at 90° C. for 18 hours. The reaction mixture wasconcentrated in vacuo, water and 10% methanol in DCM were added and theorganic layer separated, dried (MgSO4), filtered and concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 5-100% ethyl acetate in cyclohexane) to give(S)-2-{2-[2-(2,2,2-Trifluoro-ethyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-propionicacid tert-butyl ester (150 mg, 65%). LCMS: RT=3.74 min, [M+H]+=479. ¹HNMR 300 MHz (DMSO-d): δ 8.22 (1 H, d, J=8.79 Hz), 7.92 (1 H, s), 7.62 (1H, s), 6.44 (1 H, dd, J=8.81, 2.44 Hz), 6.20 (1 H, d, J=2.40 Hz), 5.73(2 H, t, J=8.31 Hz), 4.42-4.41 (4 H, m), 4.01 (1 H, m), 2.04 (3 H, s),1.47 (9 H, s).

Step 2:(S)-2-{2-[2-(2,2,2-Trifluoro-ethyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamonio}-propionicacid trifluoroacetate salt

(S)-2-{2-[2-(2,2,2-trifluoro-ethyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamonio}-propionicacid tert-butyl ester was converted to(S)-2-{2-[2-(2,2,2-Trifluoro-ethyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamonio}-propionicacid trifluoroacetate salt. LCMS: RT=2.86 min, [M+H]+=423.

Step 3

HATU (179 mg, 0.47 mmol), ammonium chloride (50 mg, 0.942 mmol) andtriethylamine (0.22 mL, 1.57 mmol) were added to a solution of(S)-2-{2-[2-(2,2,2-trifluoro-ethyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamonio}-propionicacid trifluoroacetate salt (168 mg, 0.314 mmol) in DMF (3 mL) andstirred for 18 hours. The reaction mixture was concentrated in vacuo andthe residue treated with ethyl acetate and water, the organics layerseperated, dried (Na2SO4), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO2, gradient0 to 10% methanol in DCM), then trituration in water to give 529 (39 mg,30%). LCMS: RT=3.23 min, [M+H]+=422. ¹H NMR 400 MHz (DMSO-d6): δ 8.05 (1H, s), 7.91 (1 H, s), 7.40 (1 H, br, s), 7.01 (1 H, br, s), 6.46 (1 H,dd, J=8.86, 2.33 Hz), 6.25 (1 H, d, J=7.11 Hz), 6.13 (1 H, d, J=2.29Hz), 5.92 (2 H, q, J=8.89 Hz), 4.46-4.39 (4 H, m), 3.81 (1 H, t, J=6.96Hz), 1.32 (3 H, d, J=6.87 Hz)

Example 530trans-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)cyclopropanecarboxamide530 Step 1:2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopropanecarboxylicacid ethyl ester

Ethyl diazoacetate (3.49 g, 61.3 mmol) was added over 20 minutes to astirred suspension of palladium (II) acetate (61 mmol) and vinylboronicacid pinacol ester (1.9 g, 12.26 mmol) in diethyl ether (30 mL) andstirred for 2 hours. The reaction was concentrated in vacuo and theresidues distilled under vacuum (100-140° C. at 0.5-1 mbar) to afford2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopropanecarboxylicacid ethyl ester (3.08 g, quant.) as a 4:6 mix of products, cis/transisomers. ¹H NMR 300 MHz (CHCl3-d): δ 4.26-4.25 (0.8 H, m), 4.12-4.12(1.2 H, m), 1.83-1.82 (0.4 H, m), 1.76-1.75 (0.6 H, m), 1.28-1.27 (6 H,m), 1.26 (6 H, m), 1.22 (3 H, m), 1.16-1.05 (0.8 H, m), 1.01-1.00 (1.2H, m), 0.58 (0.6 H, ddd, J=10.25, 7.44, 5.18 Hz), 0.41-0.41 (0.4 H, m)

Step 2: Racemiccis/trans-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-cyclopropanecarboxylicacid ethyl ester

A vessel was charged with8-bromo-2-[4-(2,2,2-trifluoro-ethyl)-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene(500 mg, 1.2 mmol),2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopropanecarboxylicacid ethyl ester (300 mg, 1.25 mmol), PdCl2dppf.DCM (92.5 mg, 0.125mmol, 10 mol %), cesium carbonate (3.88 g, 11.9 mmol), 1,4-dioxane (10mL) and water (2.5 mL). The reaction vessel was evacuated and refilledwith nitrogen before being stirred at 110° C. for 18 hours. The reactionmixture was concentrated in vacuo and the residue diluted with waterbefore adjusting to pH 6 with 1M HCl. The mixture was extracted withethyl acetate and the combined organic extracts were dried (MgSO4),filtered and concentrated in vacuo. The resultant residue was subjectedto flash chromatography (SiO2, gradient 0-5% methanol in DCM) to giveRacemiccis/trans-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-cyclopropanecarboxylicacid ethyl ester (265 mg, 49%) as a 1:1 mix of products. LCMSRT=3.58/3.68 min, [M+H]+=448. ¹H NMR 300 MHz (CHCl3-d): δ 8.34 (1 H, dd,J=8.33, 3.28 Hz), 7.94 (1 H, s), 7.70 (1 H, d, J=2.72 Hz), 7.06 (0.5 H,m), 6.98 (0.5 H, s), 6.88 (0.5 H, m) 6.79 (0.5 H, d, J=1.82 Hz), 5.73 (2H, d, J=8.37 Hz), 4.46 (4 H, d, J=7.93 Hz), 4.18-4.17 (2 H, m), 3.95 (1H, dd, J=7.12, 1.58 Hz), 2.11 (0.5 H, m), 1.94 (0.5 H, m), 1.72 (1H, m),1.37 (1 H, m), 1.29 (1.5 H, t, J=7.14 Hz), 1.07 (1.5 H, t, J=7.12 Hz)

Step 3: Racemiccis/trans-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-cyclopropanecarboxylicacid

2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-cyclopropanecarboxylicacid ethyl ester was converted to a 1:1 mix of Racemiccis/trans-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-cyclopropanecarboxylicacid. LCMS: RT=3.01 min, [M+H]+=420. ¹H NMR 300 MHz (CHCl3-d): δ ¹H NMRδ (ppm)(CHCl-d): 8.34 (0.5 H, d, J=8.33 Hz), 8.29 (0.5 H, d, J=8.30 Hz),7.96 (0.5 H, s), 7.95 (0.5 H, s), 7.73 (0.5 H, s), 7.68 (0.5 H, s), 7.08(0.5 H, m), 6.93 (0.5 H, s), 6.87 (0.5 H, m), 6.78 (0.5 H, s), 5.72 (2H, m), 4.45 (2 H, m), 4.26 (2 H, m), 2.56 (1H, m), 2.18 (0.5 H, m), 1.94(0.5 H, m), 1.70 (1H, m), 1.41 (1H, m)

Step 4

Following the amidation procedure from Example 529,2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4-triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-cyclopropanecarboxylicacid was converted to 530 after separation of cis diastereomer (528).LCMS: RT=3.47 min, [M+H]+=419. ¹H NMR 400 MHz (DMSO-d6): δ 8.25 (1 H, d,J=8.34 Hz), 8.07 (1 H, s), 8.04 (1 H, s), 7.57 (1 H, br, s), 6.94 (1 H,br, s), 6.92 (1 H, d, J=3.76 Hz), 6.81 (1 H, d, J=1.78 Hz), 5.89 (2 H,q, J=8.88 Hz), 4.54-4.44 (4H, m), 2.25-2.19 (1 H, m), 1.89 (1 H, dt,J=8.50, 4.71 Hz), 1.34-1.33 (1 H, m), 1.24-1.23 (1 H, m)

Example 538(2S)-1-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidine-2-carboxamide538 Step 1:(S)-1-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-azetidine-2-carboxylicacid

8-bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulenewas converted to(S)-1-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-azetidine-2-carboxylicacid. LCMS: RT=2.97 min, [M+H]+=435.

Step 2

Following the amidation procedure in Example 529,(S)-1-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-azetidine-2-carboxylicacid was converted to 538. LCMS: RT=3.40 min, [M+H]+=434. 1H NMR 400 MHz(MeOD): δ 8.17 (1 H, d, J=8.76 Hz), 8.05 (1 H, s), 7.94 (1 H, s), 7.52(1 H, s), 7.23 (1 H, s), 6.28 (1 H, dd, J=8.77, 2.35 Hz), 5.99 (1 H, d,J=2.31 Hz), 5.93-5.86 (2 H, m), 4.45-4.44 (4 H, m), 4.30 (1 H, dd,J=8.77, 6.81 Hz), 3.92-3.91 (1 H, m), 3.71-3.70 (1 H, m), 2.32-2.30 (1H, m)

Example 539(2S)-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylamino)propanamide539 Step 1:(S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-propionicacid

A mixture of8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene194 (0.72 g, 1.69 mmol), alanine tert-butyl ester hydrochloride (1.52 g,8.4 mmol), Rh(COD)2.BF4 (0.07 g, 0.18 mmol), diisopropylimidazoliumhydrochloride (0.07 g, 0.35 mmol) and cesium carbonate (4.38 g, 13.4mmol) in DME (7 mL) was heated at 90° C. under an argon atmosphere for16 h. The reaction mixture was concentrated in vacuo and the resultantresidue partitioned between DCM and water. The aqueous phase wasacidified with 1M HCl, extracted with 10% methanol in DCM and thecombined organic extracts dried (Na2SO4) and concentrated in vacuo togive(S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-propionicacid (0.27 g, 33%). LCMS: RT=2.47 min, [M+H]+=383.

Step 2

Following the amidation procedure in Example 529,(S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-propionicacid was converted to 539. LCMS: RT=2.77 min, [M+H]+=382. 1H NMR 400 MHz(MeOD): δ 8.10 (1 H, d, J=8.80 Hz), 7.87 (1 H, d, J=0.64 Hz), 7.76 (1 H,s), 7.39 (1 H, s), 7.01 (1 H, s), 6.44 (1 H, dd, J=8.85, 2.34 Hz), 6.21(1 H, d, J=7.11 Hz), 6.12 (1 H, d, J=2.30 Hz), 5.91-5.90 (1 H, m),4.42-4.41 (4 H, m), 3.82-3.75 (1 H, m), 1.47 (6 H, dd, J=6.59, 1.77 Hz),1.32 (3 H, d, J=6.87 Hz)

Example 542(2S)-3-methoxy-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylamino)propanamide542 Step 1:(S)-3-Methoxy-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-propionicacid

8-bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneand (S)-2-amino-3-methoxypropanoic acid hydrochloride were reacted toform(S)-3-Methoxy-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-propionicacid. LCMS: RT=2.89 min, [M+H]+=453

Step 2

Following the amidation procedure in Example 529,(S)-3-methoxy-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-propionicacid were reacted to give 542. LCMS: RT=3.29 min, [M+H]+=452. 1H NMR 400MHz (MeOD): δ 8.07 (1 H, s), 8.05 (1 H, s), 7.91 (1 H, s), 7.45 (1 H,s), 7.15 (1 H, s), 6.52 (1 H, dd, J=8.89, 2.36 Hz), 6.21-6.20 (2 H, m),5.91 (2 H, q, J=8.88 Hz), 4.45-4.43 (4 H, m), 4.00-3.99 (1 H, m), 3.57(2 H, d, J=5.63 Hz), 3.29 (3 H, s)

Example 543(2S)-1-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperazine-2-carboxamide543 Step 1:(S)-4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-piperazine-1,3-dicarboxylicacid 1-benzyl ester

8-bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneand (S)-piperazine-1,3-dicarboxylic acid 1-benzyl ester was converted to(S)-4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-piperazine-1,3-dicarboxylicacid 1-benzyl ester. LCMS: RT=3.50 min, [M+H]+=598.

Step 2:(S)-3-Carbamoyl-4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-piperazine-1-carboxylicacid benzyl ester

(S)-4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-piperazine-1,3-dicarboxylicacid 1-benzyl ester was converted to(S)-3-Carbamoyl-4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-piperazine-1-carboxylicacid benzyl ester. LCMS: RT=3.27 min, [M+H]+=597.

Step 3

A mixture of(S)-3-carbamoyl-4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-piperazine-1-carboxylicacid benzyl ester (0.03 g) and 10% Pd/C (0.014 g) in IMS (5 mL) wasstirred under an atmosphere of hydrogen at RT for 64 h. The reactionmixture was filtered through Celite® and the filtrate concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 0 to 20% methanol in DCM) to give 543 (0.005 g, 20%).LCMS: RT=2.49 min, [M+H]+463. 1H NMR 400 MHz (MeOD): δ 8.28 (1 H, d,J=9.03 Hz), 8.00 (1 H, s), 7.78 (1 H, s), 6.79 (1 H, dd, J=9.09, 2.63Hz), 6.56 (1 H, d, J=2.58 Hz), 5.83 (2 H, q, J=8.50 Hz), 4.50-4.43 (3 H,m), 4.30 (1 H, t, J=3.89 Hz), 3.52-3.45 (2 H, m), 3.38 (1 H, dd,J=13.28, 3.28 Hz), 3.34 (1 H, s), 3.13-3.10 (2 H, m), 2.96-2.88 (1 H, m)

Example 547(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methylcarbamate 547

To a solution of[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methanol(0.10 g, 0.31 mmol) in THF (1 mL) cooled to −78° C. was addedtrichloroacetyl isocyanate (40 μL, 0.47 mmol). The resultant mixture wasallowed to warm to 0° C. before triethylamine (0.17 mL) and water (0.3mL) were added and the mixture stirred at RT for 16 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Thecombined organic phases were dried (Na2SO4) and concentrated in vacuo.The resultant residue was subjected to flash chromatography (SiO2,gradient 0 to 10% methanol in DCM) to give 547 (0.095 g, 83%). LCMS:RT=3.34 min, [M+H]+=369. 1H-NMR 400 MHz (DMSO-d6): δ 8.39 (1 H, d,J=8.24 Hz), 7.92-7.92 (2 H, m), 7.11 (1 H, dd, J=8.30, 1.71 Hz), 7.02 (1H, d, J=1.63 Hz), 5.88-5.87 (1 H, m), 4.99 (2 H, s), 4.55-4.49 (4 H, m),3.29 (2 H, s), 1.48 (6 H, d, J=6.60 Hz)

Example 548(2S)-1-(2-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide548 Step 1:(S)-1-{2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-pyrrolidine-2-carboxylicacid

8-bromo-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneand L-proline were reacted to give(S)-1-{2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-pyrrolidine-2-carboxylicacid. LCMS: RT=3.06 min, [M+H]+=463.

Step 2

Following the amidation procedure in Example 529,(S)-1-{2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-pyrrolidine-2-carboxylicacid was converted to 548. LCMS: RT=3.60 min, [M+H]+462. 1H NMR 400 MHz(DMSO-d6): δ 8.14 (1 H, d, J=8.92 Hz), 7.88 (1 H, s), 7.42 (1 H, s),7.06 (1 H, s), 6.37 (1 H, dd, J=8.97, 2.45 Hz), 6.06 (1 H, d, J=2.40Hz), 5.81 (2 H, q, J=8.90 Hz), 4.48-4.40 (4 H, m), 3.98-3.97 (1 H, m),3.58-3.56 (1 H, m), 2.28 (2 H, s), 2.23-2.21 (1 H, m), 1.98-1.96 (3 H,m)

Example 5492-cyclopropyl-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)acetamide549 Step 1:Cyclopropyl-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-aceticacid methyl ester

A mixture of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol490 (0.20 g, 0.64 mmol), cyclopropyl-hydroxy-acetic acid methyl ester(0.253 g, 1.28 mmol), triphenylphopshine (0.205 g, 1.28 mmol) and DIAD(252 μL, 1.28 mmol) in dioxane (6 mL) was stirred at RT for 18 h thenconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO2, gradient 0 to 10% methanol in TBME) to giveCyclopropyl-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-aceticacid methyl ester (0.068 g, 25%). LCMS: RT=3.43 min, [M+H]+=424.

Step 2

A solution ofcyclopropyl-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-aceticacid methyl ester (0.068 g, 0.16 mmol) and 7M ammonia in methanol (20mL) was stirred at RT for 18 h then concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO2, gradient 0 to 10%methanol in ethyl acetate) to give 549 (0.033 g, 50%). LCMS: RT=3.52min, [M+H]+=409. 1H NMR 400 MHz (DMSO-d6): δ 8.28 (1 H, d, J=8.97 Hz),7.89 (1 H, d, J=0.64 Hz), 7.85 (1 H, s), 7.54 (1 H, s), 7.25 (1 H, s),6.73 (1 H, dd, J=8.99, 2.59 Hz), 6.49 (1 H, d, J=2.57 Hz), 5.89-5.88 (1H, m), 4.52-4.44 (4 H, m), 3.97 (1 H, d, J=8.20 Hz), 1.48 (3 H, d,J=1.16 Hz), 1.46 (3 H, d, J=1.16 Hz), 1.26-1.25 (1 H, m), 0.61-0.54 (3H, m), 0.44-0.43 (1 H, m)

Example 5502-cyclopropyl-2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)acetamide550 Step 1:(S)-2-{[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methyl-amino}-propionicacid tert-butyl ester

To a solution of(S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-propionicacid tert-butyl ester (0.24 g, 0.55 mmol) in DCE (7 mL) was addedaqueous formaldehyde (4.4 mL, 55.4 mmol, 37% solution) and sodiumtriacetoxyborohydride (7.2 g, 34.0 mmol) portion wise over 58 h. Theresulting mixture was then washed with saturated aqueous sodiumcarbonate and the aqueous phase extracted with further DCM. The combinedorganic phases were dried (Na2SO4) and concentrated in vacuo to give(S)-2-{[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methyl-amino}-propionicacid tert-butyl ester (0.24 g, 97%). LCMS: RT=3.81 min, [M+H]+=453.

Step 2

(S)-2-{[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methyl-amino}-propionicacid tert-butyl ester (0.24 g, 0.53 mmol) and TFA (2.5 mL) in DCM (2.5mL) was stirred at RT for 5 h then concentrated in vacuo. The resultantresidue was triturated with diethyl ether and pentane to give 550 (0.269g, quant.). LCMS: RT=2.70 min, [M+H]+=397

Example 551(2S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidine-2-carboxamide551 Step 1:(S)-1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-,3a-diaza-benzo[e]azulen-8-yl]-azetidine-2-carboxylicacid

A mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 (0.27 g, 0.72 mmol), (L)-azetidine-2-carboxlic acid (0.73 g, 7.2mmol), copper (I) iodide (0.057 g, 0.3 mmol) and potassium phosphate(1.83 g, 8.64 mmol) in DMSO (6 mL) was heated under argon at 80° C. for18 h. The reaction mixture was cooled to RT, filtered through Celite®then loaded onto an SCX-2 cartridge, washed with dioxane and eluted with2M ammonia in methanol. Basic fractions were combined and concentratedin vacuo and the resultant residue was subjected to flash chromatography(C18, gradient 20 to 60% methanol (containing 0.2M ammonia) in water) togive(S)-1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-,3a-diaza-benzo[e]azulen-8-yl]-azetidine-2-carboxylicacid (0.158 g, 56%). LCMS: RT=2.60 min, [M+H]+=395.

Step 2

Following the amidation procedure in Example 529,(S)-1-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-,3a-diaza-benzo[e]azulen-8-yl]-azetidine-2-carboxylicacid was converted to 551. LCMS: RT=3.01 min, [M+H]+=394. 1H NMR 400 MHz(DMSO-d6): δ 8.22 (1 H, d, J=8.74 Hz), 7.88 (1 H, d, J=0.64 Hz), 7.80 (1H, s), 7.53 (1 H, s), 7.24 (1 H, s), 6.27 (1 H, dd, J=8.76, 2.35 Hz),5.99 (1 H, d, J=2.32 Hz), 5.91-5.90 (1 H, m), 4.47-4.43 (4 H, m), 4.30(1 H, dd, J=8.76, 6.88 Hz), 3.93-3.92 (1 H, m), 3.71 (1 H, q, J=7.77Hz), 2.54-2.46 (1 H, m), 2.34-2.27 (1 H, m), 1.48 (3 H, d, J=3.26 Hz),1.46 (3 H, d, J=3.28 Hz)

Example 5521-((2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methyl)-1-methylurea552 Step 1:2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbaldehyde

A solution of[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methanol(0.294 g, 0.91 mmol) and Dess-Martin periodinane (3.32 mL, 1.0 mmol, 3Msolution in DCM) in DCM (15 mL) was stirred at RT for 1.5 h then washedwith 1M sodium hydroxide. The aqueous phase was extracted with DCM andthe combined organic extracts dried (Na2SO4) and concentrated in vacuoto give2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbaldehyde(0.35 g, quant.). LCMS: RT=3.07 min, [M+H]+=324.

Step 2:[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylmethyl]-methyl-amine

A mixture of2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbaldehyde(0.35, 0.90 mmol), methylamine (0.9 mL, 1.80 mmol, 2M solution in THF)and 4 Å molecular sieves in CHCl3 were stirred at RT for 1.5 h beforesodium triacetoxyborohydride (0.57 g, 2.7 mmol) was added. The resultantmixture was stirred for 16 h then washed with saturated aqueous sodiumbicarbonate. The aqueous phase was extracted with 10% methanol in DCMand the combined organic phases dried (Na2SO4) and concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO2, gradient 0 to 20% methanol in DCM) to give[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylmethyl]-methyl-amine(109 mg, 36%). LCMS: RT=1.90 min, [M+H]+=339

Step 3

A solution of[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylmethyl]-methyl-amine(0.106 g, 0.31 mmol) and trimethylsilyl isocyanate (87 μL, 0.56 mmol) inDCM (4 mL) was stirred at RT for 1.5 h then washed with water. Theaqueous phase was extracted with DCM and the combined organics dried(Na2SO4) and concentrated in vacuo. The resultant residue was trituratedwith diethyl ether to give 552 (0.101 g, 85%). LCMS: RT3.07 min,[M+H]+=382. 1H NMR 400 MHz (DMSO-d6): δ 8.36 (1 H, d, J=8.23 Hz),7.90-7.90 (2 H, m), 6.99 (1 H, dd, J=8.28, 1.71 Hz), 6.86 (1 H, d,J=1.63 Hz), 5.96 (2 H, s), 5.89-5.88 (1 H, m), 4.53-4.47 (4 H, m), 4.39(2 H, s), 2.76 (3 H, s), 1.48 (6 H, d, J=6.60 Hz)

Example 553(2S)-1-(2-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidine-2-carboxamide553 Step 1(S)-1-{2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-azetidine-2-carboxylicacid

Following the procedure in Example 551,8-bromo-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneand (L)-azetidine-2-carboxylic acid were reacted to give(S)-1-{2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-azetidine-2-carboxylicacid. LCMS: RT=2.93 min, [M+H]+=449

Step 2

Following the amidation procedure in Example 529,(S)-1-{2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-azetidine-2-carboxylicacid was converted to 553. LCMS: RT=3.45 min, [M+H]+=448. 1H NMR 400 MHz(DMSO-d6): δ 8.15 (1 H, d, J=8.75 Hz), 7.89 (1 H, s), 7.53 (1 H, s),7.23 (1 H, s), 6.27 (1 H, dd, J=8.78, 2.35 Hz), 5.98 (1 H, d, J=2.31Hz), 5.81-5.79 (2 H, m), 4.43-4.42 (3 H, m), 4.30 (1 H, dd, J=8.76, 6.83Hz), 3.93-3.92 (1 H, m), 3.71 (1 H, q, J=7.78 Hz), 2.36-2.29 (1 H, m),2.27 (3 H, s)

Example 5552-(1-isopropyl-1H-1,2,4-triazol-5-yl)-10-phenyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine555

A mixture of10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.5 mmol), phenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by theaddition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled withN2 gas for 10 min, the reaction tube was sealed, and the contents werestirred at 130° C. under microwave irradiation for 30 min. The mixturewas filtered through celite and the filtrate was concentrated andpurified with prep-HPLC to give 555 (19.8 mg, 12%). 1H-NMR (DMSO, 400MHz): δ 8.70 (s, 1H), 7.93 (d, J=14.4 Hz, 2H), 7.61-7.66 (m, 3H),7.46-7.50 (m, 2H), 7.34-7.38 (m, 1H), 7.14 (d, J=8.4 Hz, 2H), 5.75-5.79(m, 1H), 4.54-4.56 (m, 4H), 1.50 (d, J=7.6 Hz, 6H)

Example 5561-isopropyl-5-(10-phenyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-amine556

A mixture of5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine(0.5 mmol), phenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by theaddition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled withN2 gas for 10 min, the reaction tube was sealed, and the contents werestirred at 130° C. under microwave irradiation for 30 min. The mixturewas filtered through celite and the filtrate was concentrated andpurified with prep-HPLC to give 556 (31 mg, 18%). 1H-NMR (DMSO, 400MHz): δ 8.68 (s, 1H), 8.16 (s, 1H), 7.64-7.68 (m, 3H), 7.38-7.50 (m,2H), 7.34-7.37 (m, 1H), 7.17 (d, J=8.4 Hz, 2H), 5.49-5.55 (m, 1H),4.54-4.60 (m, 4H), 1.46 (d, J=6.8 Hz, 6H)

Example 5572-(1-isopropyl-1H-1,2,4-triazol-5-yl)-10-(pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine557

A mixture of10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.5 mmol), pyrimidin-5-ylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed bythe addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbledwith N2 gas for 10 min, the reaction tube was sealed, and the contentswere stirred at 130° C. under microwave irradiation for 30 min. Themixture was filtered through celite and the filtrate was concentratedand purified with prep-HPLC to give 557 (39 mg, 13%). 1H-NMR (CDCl3, 400MHz): δ 9.23 (s, 1H), 9.01 (s, 2H), 8.78 (s, 1H), 7.89 (s, 1H), 7.69 (s,1H), 7.53-7.53 (d, J=2.4 Hz 1H), 7.52-7.51 (d, J=2.4 Hz 1H), 5.90-5.83(m, 1H), 4.58-4.56 (m, 2H), 4.53-4.51. MS (ESI) m/z 374.17 [M+H+]

Example 5581-isopropyl-5-(10-(pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-amine558

A mixture of5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine(0.5 mmol), pyrimidin-5-ylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed bythe addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbledwith N2 gas for 10 min, the reaction tube was sealed, and the contentswere stirred at 130° C. under microwave irradiation for 30 min. Themixture was filtered through celite and the filtrate was concentratedand purified with prep-HPLC to give 558 (65.8 mg, 16.9%). 1H-NMR (CDCl3,400 MHz): δ 9.22 (s, 1H), 9.00 (s, 2H), 8.77 (s, 1H), 7.582 (s, 1H),7.53-7.52 (d, J=2.4 Hz, 1H), 7.50-7.50 (d, J=2.4 Hz, 1 H), 5.74-5.68 (m,1H), 4.57-4.55 (m, 2H), 4.49-4.48 (m, 2H), 4.05 (s, 2H). MS (ESI) m/z389.18 [M+H+]

Example 5591-(2-chlorophenyl)-5-(10-(pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-amine559

A mixture of5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-amine(0.5 mmol), pyrimidin-5-ylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed bythe addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbledwith N2 gas for 10 min, the reaction tube was sealed, and the contentswere stirred at 130° C. under microwave irradiation for 30 min. Themixture was filtered through celite and the filtrate was concentratedand purified with prep-HPLC to give 559 (38.2 mg, 8.3%). 1H-NMR (CDCl3,400 MHz): δ 9.22 (s, 1H), 8.79 (s, 2H), 8.01 (s, 1H), 7.55-7.42 (m, 6H)7.00-7.07 (d, J=8 Hz, 1H), 4.45 (s, 2H), 4.41 (s, 2H), 4.258 (s, 2H). MS(ESI) m/z 457.12 [M+H+]

Example 56010-(4-chlorophenyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine560

A mixture of10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.5 mmol), 4-chlorophenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed bythe addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbledwith N2 gas for 10 min, the reaction tube was sealed, and the contentswere stirred at 130° C. under microwave irradiation for 30 min. Themixture was filtered through celite and the filtrate was concentratedand purified with prep-HPLC to give 560 (40.5 mg, 10%). 1H NMR (CDCl3,400 MHz): δ 8.7-8.7 (d, J=2.4 Hz, 1H), 7.96 (s, 1H), 7.90 (s, 1H)7.57-7.43 (m, 5H), 7.15-7.13 (d, J=8.8 Hz, 1H), 5.94 (m, 1H), 4.56-4.54(d, J=5.6 Hz, 2H), 4.56-4.54 (d, J=5.6 Hz, 2H), 1.62 (s, 6H). MS (ESI)m/z 406.14 [M+H+]

Example 5615-(10-(4-chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine561

A mixture of5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine(0.5 mmol), 4-chlorophenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed bythe addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbledwith N2 gas for 10 min, the reaction tube was sealed, and the contentswere stirred at 130° C. under microwave irradiation for 30 min. Themixture was filtered through celite and the filtrate was concentratedand purified with prep-HPLC to give 561 (76.4 mg, 18.1%). 1H NMR (CDCl3,400 MHz): δ8.71-8.69 (d, J=2.4 Hz, 1H), 7.63 (s, 1H), 7.56-7.43 (m, 5H),7.12-7.10 (d, J=8.8 Hz, 1H), 5.75 (m, 1H), 4.52-4.51 (d, J=5.6 Hz, 2H),4.46-4.45 (d, J=5.6 Hz, 2H), 4.13 (s, 2H), 1.53-1.51 (s, J=6.4 Hz, 6H).MS (ESI) m/z 420.15 [M+H+]

Example 56210-(4-chlorophenyl)-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine562

A mixture of10-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.5 mmol), 4-chlorophenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed bythe addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbledwith N2 gas for 10 min, the reaction tube was sealed, and the contentswere stirred at 130° C. under microwave irradiation for 30 min. Themixture was filtered through celite and the filtrate was concentratedand purified with prep-HPLC to give 562 (79.7 mg, 16.8%). 1H NMR (CDCl3,400 MHz): δ 8.12 (s, 1H), 8.02 (s, 1H), 8.01 (s, 1H), 7.66-7.52 (dd,J=16 Hz, 2H), 7.46-7.04 (m, 7H), 7.04-7.02 (d, J=8 Hz, 1H), 7.11-7.09(d, J=8 Hz, 1H), 4.46-4.44 (d, J=8 Hz, 4H). MS (ESI) m/z 474.08 [M+H+]

Example 5632-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-10-phenyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine563

A mixture of10-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.5 mmol), phenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by theaddition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled withN2 gas for 10 min, the reaction tube was sealed, and the contents werestirred at 130° C. under microwave irradiation for 30 min. The mixturewas filtered through celite and the filtrate was concentrated andpurified with prep-HPLC to give 563 (82 mg, 38%). 1H-NMR (DMSO, 400MHz): δ 8.18 (s, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.38-7.70 (m, 10H),7.14 (d, J=7.6 Hz, 1H), 4.45-4.51 (m, 4H)

Example 5641-(2-chlorophenyl)-5-(10-phenyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-amine564

A mixture of5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-amine(0.5 mmol), phenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by theaddition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled withN2 gas for 10 min, the reaction tube was sealed, and the contents werestirred at 130° C. under microwave irradiation for 30 min. The mixturewas filtered through celite and the filtrate was concentrated andpurified with prep-HPLC to give 564 (47 mg, 21%). 1H-NMR (DMSO, 400MHz): δ 7.90 (s, 1H), 8.89 (s, 1H), 7.38-7.70 (m, 10H), 7.03 (d, J=10.8Hz, 1H), 5.48 (s, 2H), 4.43-4.49 (m, 4H)

Example 5652-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-10-(pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine565

A mixture of10-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(0.5 mmol), pyrimidin-5-ylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed bythe addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbledwith N2 gas for 10 min, the reaction tube was sealed, and the contentswere stirred at 130° C. under microwave irradiation for 30 min. Themixture was filtered through celite and the filtrate was concentratedand purified with prep-HPLC to give 565 (283 mg, 64.2%). 1H NMR (CDCl3,400 MHz): δ 9.25 (s, 1H), 8.81(s, 2H), 8.09-8.01 (m, 2H), 7.54 (s, 1H),7.19-7.47 (m, 3H), 7.43-7.41 (dd, J=8 Hz, 2H), 7.11-7.09 (d, J=8 Hz,1H), 4.47-4.45 (d, J=8 Hz, 4H), MS (ESI) m/z 442.11 [M+H+]

Example 5661-(2-chlorophenyl)-5-(10-(4-chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-amine566

A mixture of5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-amine(0.5 mmol), 4-chlorophenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed bythe addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbledwith N2 gas for 10 min, the reaction tube was sealed, and the contentswere stirred at 130° C. under microwave irradiation for 30 min. Themixture was filtered through celite and the filtrate was concentratedand purified with prep-HPLC to give 566 (200 mg, 42.2%). 1H NMR (CDCl3,400 MHz): δ 8.06 (s, 1H), 7.56-7.37 (m, 10H), 7.03-7.00 (d, J=8.0 Hz,2H) 4.44 (s, 2 H), 4.39 (s, 2 H), 4.21 (s, 2H). MS (ESI) m/z 474.08[M+H+]

Example 5679-(4-chlorophenyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine567

To a mixture of9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine194 (300 mg, 0.80 mmol), 4-chlorophenylboronic acid (188 mg, 1.21 mmol),Pd(dppf)Cl2 (65 mg, 0.080 mmol) and Cs2CO3 (314 mg, 0.96 mmol) in amicrowave reaction tube, dioxane/H2O (5 ml) was added and argon wasbubbled through. The reaction mixture was heated under microwaveirradiation at 130 C for 30 min. The reaction mixture was filtered,concentrated, and purified by HPLC to give 567 (68.4 mg, 21%). 1H NMR(DMSO, 400 MHz) δ 8.46 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.90 (s, 1H),7.74 (d, J=6.4 Hz, 2H), 7.51-7.46 (m, 3H), 2.34 (s, 1H), 5.95-5.84 (m,1H), 4.53 (s, 4H), 1.46 (d, J=6.8 Hz, 6H). LCMS (ESI): m/z 406.0 (M+H+)

Example 5689-(4-chlorophenyl)-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine568 Step 1:9-bromo-N-formyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine, fromExample 43, (1.0 g, 2.56 mmol), Pd(dppf)Cl2(104 mg, 0.128 mmol) and DMAP(363 mg, 2.56 mmol) were combined in a flask, and HCONH2 (30 ml) wasadded. The resulting mixture was stirred at 70° C. for 5 h. The reactionmixture was cooled to room temperature, diluted with EtOAc, andfiltered. The solid was collected to give9-bromo-N-formyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide(400 mg, 46%). LCMS (ESI) m/z 335.8 (M+H+)

Step 2:9-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

To a solution of9-bromo-N-formyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide(350 mg, 1.04 mmol) in HOAc (10 ml) was added (2-chlorophenyl)hydrazinehydrochloride (557 mg, 3.13 mmol) in one portion. The resulting mixturewas stirred at 80° C. for 4 h. The reaction mixture was cooled to roomtemperature and concentrated. The residue was dissolved in MeOH andpurified by chromatography on silica gel (Hexanes:EtOAc=10:1-1:1) togive9-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(300 mg, 65%). LCMS (ESI): m/z 443.7 (M+H+)

Step 3

9-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(300 mg, 0.88 mmol) 4-chlorophenylboronic acid (188 mg, 1.20 mmol),Cs2CO3 (314 mg, 0.96 mmol) and dioxane/water (3:1, 5 ml) were combinedin a tube. Pd(dppf)Cl2 (65 mg, 0.08 mmol) was added and N2 was bubbledthrough the solution. The mixture was heated in the microwave reactor at130° C. for 30 min. The reaction mixture was filtered. The filtrate wasconcentrated, and purified by HPLC to give 568 (86 mg, 20%). 1H NMR(DMSO, 400 MHz) δ 8.17 (s, 1H), 7.88 (s, 1H), 7.70 (d, J=8.4 Hz, 3H),7.64-7.60 (m, 3H), 7.54 (d, J=6.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H),7.25-7.20 (m, 2H), 4.44 (s, 4H). LCMS (ESI): m/z 470.0 (M+H+)

Example 5695-(9-(4-chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine569 Step 1: methyl9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate

9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (5.0 g,12.8 mmol), Pd(dppf)Cl2 (0.52 g, 0.64 mmol) and DMAP (1.82 g, 12.8 mmol)were mixed in MeOH (150 ml). The reaction mixture was stirred at 60° C.overnight. The reaction mixture was cooled to room temperature, andfiltered. The solid was collected to give methyl9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylatewith a purity of 94% (3.5 g). 1H NMR (DMSO, 400 MHz) δ 8.27 (d, J=8.4Hz, 1H), 8.05 (s, 1H), 7.28 (d, J=8.8 Hz, 1H ), 7.24(s, 1H ), 4.46(s,4H), 3.74 (s, 3H ). LCMS (ESI) m/z 324.7 (M+H+)

Step 2:9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylicacid

methyl9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate(3.5 g, 10.8 mmol) and LiOH (0.52 g, 21.7 mmol) were dissolved in amixture of THF:H2O (1:1, 150 mL). After the resulting mixture wasstirred at 70° C. for 2 h, the water phase of the reaction mixture wasseparated, adjusted to pH 4.0 and extracted with EtOAc (100 mL×4). Theorganic phase was pooled and concentrated to give product (3.0 g,90.5%). LCMS (ESI): m/z 310.6 (M+H+)

Step 3: methylN′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate

9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylicacid (3.2 g, 10.4 mmol), methyl N-Boc-carbamimidothioate (4.7 g, 12.4mmol), HATU (5.0 g, 26.0 mmol) and DIPEA (6.7 g, 52.1 mmol) weredissolved in DCM (200 mL). After the resulting mixture was stirred atroom temperature for 2 h, the reaction mixture was concentrated andmethanol (50 mL) was added and filtered. The solid was collected to givemethylN′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate(3.0 g, 60%). 1H NMR (DMSO, 400 MHz) δ 12.84 (s, 1H), 8.31 (s, 1H), 8.18(s, 1H), 7.32-7.27 (m, 2H), 5.72 (s, 1H), 4.49 (s, 4H), 2.30 (s, 3H),1.49 (s, 9H)

Step 4:5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine

To a mixture of methylN′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate(1.2 g, 2.5 mmol) and isopropylhydrazine hydrochloride (0.55 g, 5 mmol)in DMF (50 mL), DIPEA (3.2 g, 25 mmol) was added. The resulting mixturewas stirred at 120° C. overnight. The reaction mixture was concentrated,and MeOH (30 mL) was added. The solid was collected to give5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine(430 mg, 49%). 1H NMR (DMSO, 400 MHz) δ 8.28 (d, J=8.4 Hz, 1H), 7.57 (s,1H), 7.33 (d, J=8.4 Hz, 1H), 7.26 (s, 1H), 5.69-5.66 (m, 1H), 5.35 (s,1H), 4.49 (s, 4H), 4.10 (s, 1H), 3.14 (s, 2H), 1.37 (d, J=6.8 Hz, 6H)

Step 5

After5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine(400 mg, 1.03 mmol) 4-chlorophenylboronic acid (321 mg, 2.06 mmol),Pd(dppf)Cl2 (84 mg, 0.1 mmol) and Cs2CO3 (403 mg, 1.23 mmol) werecombined in a tube, dioxane and water (3:1, 20 ml) was added. Themixture was bubbled with N2 for 10 min. The mixture was sealed to heatin the microwave reactor at 130° C. for 30 min. The reaction mixture wasfiltered. The filtrate was concentrated and purified by HPLC to give 569(74.9 mg, 17%) 1H NMR (DMSO, 400 MHz) δ 8.44 (d, J=8.4 Hz, 1H), 7.74 (d,J=9.2 Hz, 3H), 7.51-7.46 (m, 3H), 7.34 (s, 1H), 7.75-7.72 (m, 1H), 5.19(s, 2H), 4.51(s, 4H), 1.39 (d, J=6.8 Hz, 6H). LCMS (ESI) m/z 421.0(M+H+)

Example 5701-(2-chlorophenyl)-5-(9-(4-chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-amine570 Step 1:5-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-ylcarbamicacid

CH3COOH (50 ml) was added to a mixture of methylN′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate,from Example 569, (1.0 g, 2.08 mmol) and (2-chlorophenyl)hydrazinehydrochloride (0.74 g, 4.16 mmol). The resulting mixture was stirred at120° C. overnight. The reaction mixture was concentrated and purified bysilica gel chromatography (Hexanes:EtOAc, 3:1-1:1) to give5-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-ylcarbamicacid (630 mg, 60%). 1H NMR (DMSO, 400 MHz) δ 10.60 (s, 1H), 7.76 (s,1H), 7.70-7.68 (m, 1H), 7.63-7.60 (m, 2H), 7.52-7.52 (m, 1H), 7.48-7.46(m, 1H), 7.18 (s, 1H), 7.10-7.07 (m, 1H), 5.45 (s, 1H), 4.42 (s, 4H)

Step 2:1-(2-chlorophenyl)-5-(9-(4-chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-ylcarbamicacid

5-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-ylcarbamicacid (600 mg, 1.2 mmol), 4-chlorophenylboronic acid (374 mg, 2.4 mmol),Pd(dppf)Cl2(97.9 mg, 0.12 mmol) and Cs2CO3 (469 mg, 1.44 mmol) weredissolved in dioxane/H2O (3:1, 30 ml). The resulting mixture was bubbledwith N2 for 10 min and then sealed to stir at 120° C. for 4 h under N2.The reaction mixture was filtered. The filtrate was concentrated andpurified by HPLC to give1-(2-chlorophenyl)-5-(9-(4-chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-ylcarbamicacid (270 mg, 21%). 1H NMR (DMSO, 400 MHz) δ 10.65 (s, 1H), 7.74 (s,1H), 7.70 (d, J=8.4 Hz, 3H), 7.67-7.61 (m, 3H), 7.54 (t, 1H), 7.47 (d,J=8.4 Hz, 2H), 7.27-7.22 (m, 2H), 7.45-7.43 (m, 4H)

Step 3

A Solution of EtOAc/HCl (20 mL) was added to1-(2-chlorophenyl)-5-(9-(4-chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-ylcarbamicacid (270 mg, 0.6 mmol) in EtOAc (10 mL) in Portions. The resultingmixture was stirred at 50° C. for 5 h. The reaction mixture was filteredand the solid was collected to give 570 (100 mg, 34%). 1H NMR (DMSO, 400MHz) δ 7.73-7.69 (m, 5H), 7.63-7.61 (m, 2H), 7.55-7.52 (m, 1H), 7.48(dd, J=2.0, 6.8 Hz, 2H), 7.28-7.25 (m, 2H), 4.80-4.30 (b, 2H), 4.45 (s,4H). LCMS (ESI) m/z 489.1 (M+H+)

Example 901 p110α (Alpha) PI3K Binding Assay

Binding Assays: Initial polarization experiments were performed on anAnalyst HT 96-384 (Molecular Devices Corp, Sunnyvale, Calif.). Samplesfor fluorescence polarization affinity measurements were prepared byaddition of 1:3 serial dilutions of p110 alpha PI3K (Upstate CellSignaling Solutions, Charlottesville, Va.) starting at a finalconcentration of 20 ug/mL in polarization buffer (10 mM tris pH 7.5, 50mM NaCl, 4 mM MgCl2, 0.05% Chaps, and 1 mM DTT) to 10 mM PIP2(Echelon-Inc., Salt Lake City, Utah) final concentration. After anincubation time of 30 minutes at room temperature, the reactions werestopped by the addition of GRP-1 and PIP3-TAMRA probe (Echelon-Inc.,Salt Lake City, Utah) 100 nM and 5 nM final concentrations respectively.Read with standard cut-off filters for the rhodamine fluorophore(λex=530 nm; λem=590 nm) in 384-well black low volume Proxiplates(PerkinElmer, Wellesley, Mass.) Fluorescence polarization values wereplotted as a function of the protein concentration, and the EC50 valueswere obtained by fitting the data to a 4-parameter equation usingKaleidaGraph software (Synergy software, Reading, Pa.). This experimentalso establishes the appropriate protein concentration to use insubsequent competition experiments with inhibitors.

Inhibitor IC50 values were determined by addition of the 0.04 mg/mL p110alpha PI3K (final concentration) combined with PIP2 (10 mM finalconcentration) to wells containing 1:3 serial dilutions of theantagonists in a final concentration of 25 mM ATP (Cell SignalingTechnology, Inc., Danvers, Mass.) in the polarization buffer. After anincubation time of 30 minutes at room temperature, the reactions werestopped by the addition of GRP-1 and PIP3-TAMRA probe (Echelon-Inc.,Salt Lake City, Utah) 100 nM and 5 nM final concentrations respectively.Read with standard cut-off filters for the rhodamine fluorophore(λex=530 nm; λem=590 nm) in 384-well black low volume proxi plates(PerkinElmer, Wellesley, Mass.) Fluorescence polarization values wereplotted as a function of the antagonist concentration, and the IC50values were obtained by fitting the data to a 4-parameter equation inAssay Explorer software (MDL, San Ramon, Calif.).

Alternatively, inhibition of PI3K was determined in a radiometric assayusing purified, recombinant enzyme and ATP at a concentration of 1 uM.The Formula I compound was serially diluted in 100% DMSO. The kinasereaction was incubated for 1 hr at room temperature, and the reactionwas terminated by the addition of PBS. IC50 values were subsequentlydetermined using sigmoidal dose-response curve fit (variable slope).

Example 902 In vitro Cell Proliferation Assay

Efficacy of Formula I compounds was measured by a cell proliferationassay employing the following protocol (Promega Corp. Technical BulletinTB288; Mendoza et al (2002) Cancer Res. 62:5485-5488):

1. An aliquot of 100 μl of cell culture containing about 104 cells (PC3,Detroit562, or MDAMB361.1) in medium was deposited in each well of a384-well, opaque-walled plate.

2. Control wells were prepared containing medium and without cells.

3. The compound was added to the experimental wells and incubated for3-5 days.

4. The plates were equilibrated to room temperature for approximately 30minutes.

5. A volume of CellTiter-Glo Reagent equal to the volume of cell culturemedium present in each well was added.

6. The contents were mixed for 2 minutes on an orbital shaker to inducecell lysis.

7. The plate was incubated at room temperature for 10 minutes tostabilize the luminescence signal.

8. Luminescence was recorded and reported in graphs as RLU=relativeluminescence units.

Alternatively, cells were seeded at optimal density in a 96 well plateand incubated for 4 days in the presence of test compound. Alamar Blue™was subsequently added to the assay medium, and cells were incubated for6 hr before reading at 544 nm excitation, 590 nm emission. EC50 valueswere calculated using a sigmoidal dose response curve fit. The term EC50refers to the half maximal effective concentration and is theconcentration at which a drug induces a response halfway between thebaseline and maximum after some specified exposure time. It is commonlyused as a measure of drug potency.

The anti-proliferative effects of Formula I exemplary compounds weremeasured by the CellTiter-Glo® Assay against various tumor cell lines,including the following:

EC50 EC50 EC50 EC50 EC50 Mutation (μmole) (μmole) (μmole) (μmole)(μmole) Cell line Tissue Type Status 107 180 186 196 207 AU565 Breast WT0.259 0.230 0.47 0.152 3.729 BT474 Breast PI3K(amped 0.324 0.086 1.678CAL120 Breast WT 2.121 CAL51 Breast PI3K/PTEN 0.672 EFM19-2A Breast WT0.146 EVSA-T Breast PTEN 1.406 2.035 1.997 1.123 1.769 HCC1954 BreastPI3K 0.168 0.420 0.128 3.388 KPL4 Breast PI3K 0.039 0.088 0.016 1.364MCF7 Breast PI3K 0.121 MDA-MB-231 Breast K-RAS 10 MDA-MB-361.1 BreastPI3K 1.050 0.214 0.710 0.178 10 MFM223 Breast PI3K 0.439 1.099 0.2117.253 SKBR3 Breast WT 0.144 0.860 T47D Breast PI3K 0.123 0.133 0.0450.762 Colo205 Colon B-Raf 0.259 HCT116 Colon PI3K/KRAS 1.02 KM12 ColonPTEN 4.687 10 MDST8 Colon PTEN 4.009 7.789 RKO Colon PI3K 2.5 LN229Glioma PI3K 0.869 U87MG Glioma PTEN 0.787 1.019 5.769 H1703 Lung(NSCLC)WT 0.225 0.136 H2122 Lung(NSCLC) K-RAS 0.515 2.948 0.366 10 H520Lung(NSCLC) PTEN 0.264 1.287 537MEL Melanoma PTEN 2.433 A2058 MelanomaPTEN 10 9.24 A375 Melanoma B-Raf 10 10 IGROV1 Ovarian PI3K 0.06 TOV21GX1Ovarian PI3K/PTEN 3.592 PC3 Prostate PTEN 0.999 0.769 1.300 0.864 0.762

Example 903 Caco-2 Permeability

Caco-2 cells are seeded onto Millipore Multiscreen plates at 1×105cells/cm2, and cultured for 20 days. Assessment of compound permeabilityis subsequently conducted. The compounds are applied to the apicalsurface (A) of cell monolayers and compound permeation into thebasolateral (B) compartment is measured. This is performed in thereverse direction (B−A) to investigate active transport. A permeabilitycoefficient value, Papp, for each compound, a measure of the rate ofpermeation of the compound across the membrane, is calculated. Compoundsare grouped into low (Papp</=1.0×106 cm/s) or high (Papp>/=1.0×106 cm/s)absorption potential based on comparison with control compounds withestablished human absorption.

For assessment of a compound's ability to undergo active efflux, theratio of basolateral (B) to apical (A) transport compared with A to Bwas determined. Values of B−A/A−B>/=1.0 indicate the occurrence ofactive cellular efflux.

Example 904 Hepatocyte Clearance

Suspensions of cryopreserved human hepatocytes are used. Incubations areperformed at compound concentration of 1 mM or 3 μM at a cell density of0.5×106 viable cells/mL. The final DMSO concentration in the incubationis about 0.25%. Control incubations are also performed in the absence ofcells to reveal any non-enzymatic degradation. Duplicate samples (50 μL)are removed from the incubation mixture at 0, 5, 10, 20, 40 and 60minutes (control sample at 60 minutes only) and added to methanolcontaining internal standard (100 μL)—to terminate the reaction.Tolbutamide, 7-hydroxycoumarin, and testosterone may be used as controlcompounds. Samples are centrifuged and the supernatants at each timepoint pooled for analysis by LC-MSMS. From a plot of 1n peak area ratio(parent compound peak area/internal standard peak area) against time,intrinsic clearance (CLint) is calculated as follows: CLint(μl/min/million cells)=V×k, where k is the elimination rate constant,obtained from the gradient of 1n concentration plotted against time; Vis a volume term derived from the incubation volume and is expressed asuL 106 cells-1.

Example 905 Cytochrome P450 Inhibition

Formula I compounds may be screened against CYP450 targets (1A2, 2C9,2C19, 2D6, 3A4) at about 10 concentrations in duplicate, with a topconcentration of about 100 uM. Standard inhibitors (furafylline,sulfaphenazole, tranylcypromine, quinidine, ketoconazole) may be used ascontrols. Plates may be read using a BMG LabTechnologies PolarStar influorescence mode.

Example 906 Cytochrome P450 Induction

Freshly isolated human hepatocytes from a single donor may be culturedfor about 48 hr prior to addition of Formula I compound at threeconcentrations and incubated for 72 hr. Probe substrates for CYP3A4 andCYP1A2 are added for 30 minutes and 1 hr before the end of theincubation. At 72 hr, cells and media are removed and the extent ofmetabolism of each probe substrate quantified by LC-MS/MS. Theexperiment is controlled by using inducers of the individual P450sincubated at one concentration in triplicate.

Example 907 Plasma Protein Binding

Solutions of Formula I compound (5 um, 0.5% final DMSO concentration)are prepared in buffer and 10% plasma (v/v in buffer). A 96 well HTdialysis plate is assembled so that each well is divided in two by asemi-permeable cellulose membrane. The buffer solution is added to oneside of the membrane and the plasma solution to the other side;incubations are then conducted at 37° C. over 2 hr in triplicate. Thecells are subsequently emptied, and the solutions for each batch ofcompounds are combined into two groups (plasma-free andplasma-containing) then analyzed by LC-MSMS using two sets ofcalibration standards for plasma-free (6 points) and plasma-containingsolutions (7 points). The fraction unbound value for the compound iscalculated.

Example 908 hERG Channel Blockage

Formula I compounds are evaluated for ability to modulate rubidiumefflux from HEK-294 cells stably expressing hERG potassium channelsusing established flux methodology. Cells are prepared in mediumcontaining RbC1, plated into 96-well plates and grown overnight to formmonolayers. The efflux experiment is initiated by aspirating the mediaand washing each well with 3×100 μL of pre-incubation buffer (containinglow [K+]) at room temperature. Following the final aspiration, 50 μL ofworking stock (2×) compound is added to each well and incubated at roomtemperature for 10 minutes. Stimulation buffer 50 μL (containing high[K+]) is then added to each well giving the final test compoundconcentrations. Cell plates are then incubated at room temperature for afurther 10 minutes. Supernatant 80 μL from each well is then transferredto equivalent wells of a 96-well plate and analyzed via atomic emissionspectroscopy. The compound is screened as 10 pt duplicate IC50 curves,n=2, from a top concentration of 100 μM.

Example 909 In Vivo Tumor Xenograft

Animals suitable for transgenic experiments can be obtained fromstandard commercial sources. Groups of Taconic nude mice (were implantedsubcutaneously in the hind flank with MDA-MB-361.1 (PI3K mutant) breastcancer cells. Mouse xenografts were dosed daily for 21 days with drug orvehicle. Tumor sizes were recorded twice weekly over the course of thestudy. Mouse body weights were also recorded twice weekly, and the micewere observed regularly. Tumor volume was measured in two dimensions(length and width) using Ultra Cal-IV calipers (Model 54-10-111; Fred V.Fowler Co., Inc.; Newton, Mass.) and analyzed using Excel v.11.2(Microsoft Corporation; Redmond, Wash.). Tumor inhibition graphs wereplotted using KaleidaGraph, Version 3.6 (Synergy Software; Reading,Pa.). The tumor volume was calculated with formula: Tumor size(mm3)=(longer measurement×shorter measurement2)×0.5

Animal body weights were measured using an Adventurera Pro AV812 scale(Ohaus Corporation; Pine Brook, N.J.). Graphs were generated usingKaleidaGraph Version 3.6. Percent weight change was calculated usingformula: Group percent weight change=(1-(initial weight/newweight))×100.

Mice whose tumor volume exceeded 2000 mm3 or whose body weight losswas >20% of their starting weight were promptly euthanized according toregulatory guidance.

The percent tumor growth inhibition (% INH) at the end of study (EOS)was calculated using formula: % INH=100×(EOS mean volume of tumors inanimals given vehicle−EOS mean volume of tumors in animals given thedrug)/EOS mean volume of tumors in animals given vehicle.

Tumor incidence (TI) was determined based on the number of measurabletumors remaining in each group at the end of the study. A partialresponse (PR) was defined as a >50% but <100% reduction in tumor volume,compared with the starting tumor volume, observed on any day of thestudy. A complete response (CR) was defined as a 100% reduction in tumorvolume, compared with the initial tumor volume, observed on any day ofthe study. Data were analyzed and p-values were determined using theDunnett's test with JMP statistical software, version 5.1.2 (SASInstitute; Cary, N.C.). Individual tumor volumes at end of study andmean tumor volume±SEM values were calculated using JMP statisticalsoftware, version 5.1.2. Body weight data were graphed based on the meanpercentage of change from initial body weights±SEM.

Example 910 Phospho AKT Induction Assay

In a 6-well tissue culture plate cells were seeded at 5×105 cells perwell overnight. Cells were treated with an EC80 of the Formula Icompound. Following treatment, cells were washed once with cold PBS andlysed in 1× Cell Extraction Buffer from Biosource (Carlsbad, Calif.)supplemented with protease inhibitors (Roche, Mannheim, Germany), 1 mMPMSF, and Phosphatase Inhibitor Cocktails 1 and 2 from Sigma (St. Louis,Mo.). Determination of protein concentration was performed using thePierce BCA Protein Assay Kit (Rockford, Ill.). Levels of pAkt (Ser473)and total Akt were assessed using bead kits from Biosource (Carlsbad,Calif.) and the Luminex Bio-Plex system (Bio-Rad, Hercules, Calif.).

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

We claim:
 1. A compound having the structure:


2. A compound having the structure:


3. A compound having the structure:


4. A compound having the structure: